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Maková B, Mik V, Lišková B, Drašarová L, Medvedíková M, Hořínková A, Vojta P, Zatloukal M, Plíhalová L, Hönig M, Doležal K, Forejt K, Oždian T, Hajdúch M, Strnad M, Voller J. Correction of aberrant splicing of ELP1 pre-mRNA by kinetin derivatives - A structure activity relationship study. Eur J Med Chem 2025; 284:117176. [PMID: 39756144 DOI: 10.1016/j.ejmech.2024.117176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 12/14/2024] [Accepted: 12/15/2024] [Indexed: 01/07/2025]
Abstract
Familial dysautonomia is a debilitating congenital neurodegenerative disorder with no causative therapy. It is caused by a homozygous mutation in ELP1 gene, resulting in the production of the transcript lacking exon 20. The compounds studied as potential treatments include the clinical candidate kinetin, a plant hormone from the cytokinin family. We explored the relationship between the structure of a set of kinetin derivatives (N = 72) and their ability to correct aberrant splicing of the ELP1 gene. Active compounds can be obtained by the substitution of the purine ring with chlorine and fluorine at the C2 atom, with a small alkyl group at the N7 atom, or with diverse groups at the C8 atom. On the other hand, a substitution at the N3 or N9 atoms resulted in a loss of activity. We successfully tested a hypothesis inspired by the remarkable tolerance of the position C8 to substitution, postulating that the imidazole of the purine moiety is not required for the activity. We also evaluated the activity of phytohormones from other families, but none of them corrected ELP1 mRNA aberrant splicing. A panel of in vitro ADME assays, including evaluation of transport across model barriers, stability in plasma and in the presence of liver microsomal fraction as well as plasma protein binding, was used for an initial estimation of the potential bioavailability of the active compounds. Finally, a RNA-seq data suggest that 8-aminokinetin modulates expression spliceosome components.
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Affiliation(s)
- Barbara Maková
- Laboratory of Experimental Biology, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic
| | - Václav Mik
- Laboratory of Experimental Biology, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic
| | - Barbora Lišková
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic
| | - Lenka Drašarová
- Isotope Laboratory, Institute of Experimental Botany, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 00 Prague 4, Czech Republic
| | - Martina Medvedíková
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic
| | - Alena Hořínková
- Laboratory of Experimental Biology, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic
| | - Petr Vojta
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic; University of Natural Resources and Life Sciences, Vienna, Department of Biotechnology, Institute of Computational Biology, Vienna, Austria
| | - Marek Zatloukal
- Department of Chemical Biology, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic
| | - Lucie Plíhalová
- Department of Chemical Biology, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic
| | - Martin Hönig
- Department of Chemical Biology, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic
| | - Karel Doležal
- Department of Chemical Biology, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic; Laboratory of Growth Regulators, Institute of Experimental Botany AS CR & Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic
| | - Kristýna Forejt
- Laboratory of Experimental Biology, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic
| | - Tomáš Oždian
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic
| | - Marián Hajdúch
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic
| | - Miroslav Strnad
- Laboratory of Growth Regulators, Institute of Experimental Botany AS CR & Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic
| | - Jiří Voller
- Laboratory of Experimental Biology, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic.
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Jiang J, Zhang Y, Wang J, Qin Y, Zhao C, He K, Wang C, Liu Y, Feng H, Cai H, He S, Li R, Galstyan DS, Yang L, Lim LW, de Abreu MS, Kalueff AV. Using Zebrafish Models to Study Epitranscriptomic Regulation of CNS Functions. J Neurochem 2025; 169:e16311. [PMID: 39825734 DOI: 10.1111/jnc.16311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/18/2024] [Accepted: 12/30/2024] [Indexed: 01/20/2025]
Abstract
Epitranscriptomic regulation of cell functions involves multiple post-transcriptional chemical modifications of coding and non-coding RNA that are increasingly recognized in studying human brain disorders. Although rodent models are presently widely used in neuroepitranscriptomic research, the zebrafish (Danio rerio) has emerged as a useful and promising alternative model species. Mounting evidence supports the importance of RNA modifications in zebrafish CNS function, providing additional insights into epitranscriptomic mechanisms underlying a wide range of brain disorders. Here, we discuss recent data on the role of RNA modifications in CNS regulation, with a particular focus on zebrafish models, as well as evaluate current problems, challenges, and future directions of research in this field of molecular neurochemistry.
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Affiliation(s)
- Jiayou Jiang
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Yunqian Zhang
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Jiyi Wang
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Yixin Qin
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Chonguang Zhao
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Kai He
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Chaoming Wang
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Yucheng Liu
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Haoyu Feng
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Huiling Cai
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Shulei He
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Ruiyu Li
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - David S Galstyan
- Institute of Experimental Medicine, Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia
- Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
| | - Longen Yang
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Lee Wei Lim
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Murilo S de Abreu
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil
- Moscow Institute of Physics and Technology, Moscow, Russia
- Western Caspian University, Baku, Azerbaijan
| | - Allan V Kalueff
- Suzhou Municipal Key Laboratory of Neurobiology and Cell Signaling, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Moscow Institute of Physics and Technology, Moscow, Russia
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Keller MA, Nakamura M. Acetyltransferase in cardiovascular disease and aging. THE JOURNAL OF CARDIOVASCULAR AGING 2024; 4:10.20517/jca.2024.21. [PMID: 39958699 PMCID: PMC11827898 DOI: 10.20517/jca.2024.21] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/18/2025]
Abstract
Acetyltransferases are enzymes that catalyze the transfer of an acetyl group to a substrate, a modification referred to as acetylation. Loss-of-function variants in genes encoding acetyltransferases can lead to congenital disorders, often characterized by intellectual disability and heart and muscle defects. Their activity is influenced by dietary nutrients that alter acetyl coenzyme A levels, a key cofactor. Cardiovascular diseases, including ischemic, hypertensive, and diabetic heart diseases - leading causes of mortality in the elderly - are largely attributed to prolonged lifespan and the growing prevalence of metabolic syndrome. Acetyltransferases thus serve as a crucial link between lifestyle modifications, cardiometabolic disease, and aging through both epigenomic and non-epigenomic mechanisms. In this review, we discuss the roles and relevance of acetyltransferases. While the sirtuin family of deacetylases has been extensively studied in longevity, particularly through fasting-mediated NAD+ metabolism, recent research has brought attention to the essential roles of acetyltransferases in health and aging-related pathways, including cell proliferation, DNA damage response, mitochondrial function, inflammation, and senescence. We begin with an overview of acetyltransferases, classifying them by domain structure, including canonical and non-canonical lysine acetyltransferases, N-terminal acetyltransferases, and sialic acid O-acetyltransferases. We then discuss recent advances in understanding acetyltransferase-related pathologies, particularly focusing on cardiovascular disease and aging, and explore their potential therapeutic applications for promoting health in older individuals.
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Affiliation(s)
- Mariko Aoyagi Keller
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Michinari Nakamura
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
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Xu F, Byström AS, Johansson MJO. Sod1-deficient cells are impaired in formation of the modified nucleosides mcm 5s 2U and yW in tRNA. RNA (NEW YORK, N.Y.) 2024; 30:1586-1595. [PMID: 39322276 PMCID: PMC11571800 DOI: 10.1261/rna.080181.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 09/13/2024] [Indexed: 09/27/2024]
Abstract
Uridine residues present at the wobble position of eukaryotic cytosolic tRNAs often carry a 5-carbamoylmethyl (ncm5), 5-methoxycarbonylmethyl (mcm5), or 5-methoxycarbonylhydroxymethyl (mchm5) side-chain. The presence of these side-chains allows proper pairing with cognate codons, and they are particularly important in tRNA species where the U34 residue is also modified with a 2-thio (s2) group. The first step in the synthesis of the ncm5, mcm5, and mchm5 side-chains is dependent on the six-subunit Elongator complex, whereas the thiolation of the 2-position is catalyzed by the Ncs6/Ncs2 complex. In both yeast and metazoans, allelic variants of Elongator subunit genes show genetic interactions with mutant alleles of SOD1, which encodes the cytosolic Cu, Zn-superoxide dismutase. However, the cause of these genetic interactions remains unclear. Here, we show that yeast sod1 null mutants are impaired in the formation of 2-thio-modified U34 residues. In addition, the lack of Sod1 induces a defect in the biosynthesis of wybutosine, which is a modified nucleoside found at position 37 of tRNAPhe Our results suggest that these tRNA modification defects are caused by superoxide-induced inhibition of the iron-sulfur cluster-containing Ncs6/Ncs2 and Tyw1 enzymes. Since mutations in Elongator subunit genes generate strong negative genetic interactions with mutant ncs6 and ncs2 alleles, our findings at least partially explain why the activity of Elongator can modulate the phenotypic consequences of SOD1/sod1 alleles. Collectively, our results imply that tRNA hypomodification may contribute to impaired proteostasis in Sod1-deficient cells.
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Affiliation(s)
- Fu Xu
- Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden
| | - Anders S Byström
- Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden
| | - Marcus J O Johansson
- Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden
- Department of Experimental Medical Science, Lund University, 221 00 Lund, Sweden
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Hines MA, Taneyhill LA. Elp1 function in placode-derived neurons is critical for proper trigeminal ganglion development. Dev Dyn 2024:10.1002/dvdy.749. [PMID: 39381860 PMCID: PMC11978919 DOI: 10.1002/dvdy.749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/06/2024] [Accepted: 09/14/2024] [Indexed: 10/10/2024] Open
Abstract
BACKGROUND The trigeminal nerve is the largest cranial nerve and functions in somatosensation. Cell bodies of this nerve are positioned in the trigeminal ganglion, which arises from the coalescence of neural crest and placode cells. While this dual cellular origin has been known for decades, the molecular mechanisms controlling trigeminal ganglion development remain obscure. We performed RNA sequencing on the forming chick trigeminal ganglion and identified Elongator acetyltransferase complex subunit 1 (Elp1) for further study. Mutations in ELP1 cause familial dysautonomia (FD), a fatal disorder characterized by the presence of smaller trigeminal nerves and sensory deficits. While Elp1 has established roles in neurogenesis, its function in placode cells during trigeminal gangliogenesis has not been investigated. RESULTS To this end, we used morpholinos to deplete Elp1 from chick trigeminal placode cells. Elp1 knockdown decreased trigeminal ganglion size and led to aberrant innervation of the eye by placode-derived neurons. Trigeminal nerve branches also appeared to exhibit reduced axon outgrowth to target tissues. CONCLUSIONS These findings reveal a new role for Elp1 in placode-derived neurons during chick trigeminal ganglion development. These results have potential high significance to provide new insights into trigeminal ganglion development and the etiology of FD.
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Affiliation(s)
- Margaret A. Hines
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742 USA
| | - Lisa A. Taneyhill
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742 USA
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Noches V, Campos-Melo D, Droppelmann CA, Strong MJ. Epigenetics in the formation of pathological aggregates in amyotrophic lateral sclerosis. Front Mol Neurosci 2024; 17:1417961. [PMID: 39290830 PMCID: PMC11405384 DOI: 10.3389/fnmol.2024.1417961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024] Open
Abstract
The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.
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Affiliation(s)
- Veronica Noches
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Danae Campos-Melo
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Cristian A Droppelmann
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Michael J Strong
- Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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Teng H, Chen S, Liu F, Teng Y, Li Y, Liang D, Wu L, Li Z. O-Sialoglycoprotein Endopeptidase Deficiency Impairs Proteostasis and Induces Autophagy in Human Embryonic Stem Cells. Int J Mol Sci 2024; 25:7889. [PMID: 39063131 PMCID: PMC11277037 DOI: 10.3390/ijms25147889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/08/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
The OSGEP gene encodes O-sialoglycoprotein endopeptidase, a catalytic unit of the highly conserved KEOPS complex (Kinase, Endopeptidase, and Other Proteins of small Size) that regulates the second biosynthetic step in the formation of N-6-threonylcarbamoyladenosine (t6A). Mutations in KEOPS cause Galloway-Mowat syndrome (GAMOS), whose cellular function in mammals and underlying molecular mechanisms are not well understood. In this study, we utilized lentivirus-mediated OSGEP knockdown to generate OSGEP-deficient human embryonic stem cells (hESCs). OSGEP-knockdown hESCs exhibited reduced stemness factor expression and G2/M phase arrest, indicating a potential role of OSGEP in the regulation of hESC fate. Additionally, OSGEP silencing led to enhanced protein synthesis and increased aggregation of proteins, which further induced inappropriate autophagy, as evidenced by the altered expression of P62 and the conversion of LC3-I to LC3-II. The above findings shed light on the potential involvement of OSGEP in regulating pluripotency and differentiation in hESCs while simultaneously highlighting its crucial role in maintaining proteostasis and autophagy, which may have implications for human disease.
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Affiliation(s)
| | | | | | | | | | | | - Lingqian Wu
- Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 110 Xiangya Road, Changsha 410078, China; (H.T.); (S.C.); (F.L.); (Y.T.); (Y.L.); (D.L.)
| | - Zhuo Li
- Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 110 Xiangya Road, Changsha 410078, China; (H.T.); (S.C.); (F.L.); (Y.T.); (Y.L.); (D.L.)
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8
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Abbassi NEH, Jaciuk M, Scherf D, Böhnert P, Rau A, Hammermeister A, Rawski M, Indyka P, Wazny G, Chramiec-Głąbik A, Dobosz D, Skupien-Rabian B, Jankowska U, Rappsilber J, Schaffrath R, Lin TY, Glatt S. Cryo-EM structures of the human Elongator complex at work. Nat Commun 2024; 15:4094. [PMID: 38750017 PMCID: PMC11096365 DOI: 10.1038/s41467-024-48251-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
tRNA modifications affect ribosomal elongation speed and co-translational folding dynamics. The Elongator complex is responsible for introducing 5-carboxymethyl at wobble uridine bases (cm5U34) in eukaryotic tRNAs. However, the structure and function of human Elongator remain poorly understood. In this study, we present a series of cryo-EM structures of human ELP123 in complex with tRNA and cofactors at four different stages of the reaction. The structures at resolutions of up to 2.9 Å together with complementary functional analyses reveal the molecular mechanism of the modification reaction. Our results show that tRNA binding exposes a universally conserved uridine at position 33 (U33), which triggers acetyl-CoA hydrolysis. We identify a series of conserved residues that are crucial for the radical-based acetylation of U34 and profile the molecular effects of patient-derived mutations. Together, we provide the high-resolution view of human Elongator and reveal its detailed mechanism of action.
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Affiliation(s)
- Nour-El-Hana Abbassi
- Małopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Marcin Jaciuk
- Małopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
| | - David Scherf
- Institute for Biology, Department for Microbiology, University of Kassel, Kassel, Germany
| | - Pauline Böhnert
- Institute for Biology, Department for Microbiology, University of Kassel, Kassel, Germany
| | - Alexander Rau
- Bioanalytics, Institute of Biotechnology, Technical University of Berlin, Berlin, Germany
| | | | - Michał Rawski
- Małopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
- SOLARIS National Synchrotron Radiation Centre, Jagiellonian University, Krakow, Poland
| | - Paulina Indyka
- Małopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
- SOLARIS National Synchrotron Radiation Centre, Jagiellonian University, Krakow, Poland
| | - Grzegorz Wazny
- SOLARIS National Synchrotron Radiation Centre, Jagiellonian University, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland
| | | | - Dominika Dobosz
- Małopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
| | | | - Urszula Jankowska
- Małopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
| | - Juri Rappsilber
- Bioanalytics, Institute of Biotechnology, Technical University of Berlin, Berlin, Germany
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK
| | - Raffael Schaffrath
- Institute for Biology, Department for Microbiology, University of Kassel, Kassel, Germany.
| | - Ting-Yu Lin
- Małopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland.
- Department of Biosciences, Durham University, Durham, UK.
| | - Sebastian Glatt
- Małopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland.
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Martinez-Feduchi P, Jin P, Yao B. Epigenetic modifications of DNA and RNA in Alzheimer's disease. Front Mol Neurosci 2024; 17:1398026. [PMID: 38726308 PMCID: PMC11079283 DOI: 10.3389/fnmol.2024.1398026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 04/15/2024] [Indexed: 05/12/2024] Open
Abstract
Alzheimer's disease (AD) is a complex neurodegenerative disorder and the most common form of dementia. There are two main types of AD: familial and sporadic. Familial AD is linked to mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). On the other hand, sporadic AD is the more common form of the disease and has genetic, epigenetic, and environmental components that influence disease onset and progression. Investigating the epigenetic mechanisms associated with AD is essential for increasing understanding of pathology and identifying biomarkers for diagnosis and treatment. Chemical covalent modifications on DNA and RNA can epigenetically regulate gene expression at transcriptional and post-transcriptional levels and play protective or pathological roles in AD and other neurodegenerative diseases.
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Affiliation(s)
| | | | - Bing Yao
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
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Zheng X, Chen H, Deng Z, Wu Y, Zhong L, Wu C, Yu X, Chen Q, Yan S. The tRNA thiolation-mediated translational control is essential for plant immunity. eLife 2024; 13:e93517. [PMID: 38284752 PMCID: PMC10863982 DOI: 10.7554/elife.93517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/26/2024] [Indexed: 01/30/2024] Open
Abstract
Plants have evolved sophisticated mechanisms to regulate gene expression to activate immune responses against pathogen infections. However, how the translation system contributes to plant immunity is largely unknown. The evolutionarily conserved thiolation modification of transfer RNA (tRNA) ensures efficient decoding during translation. Here, we show that tRNA thiolation is required for plant immunity in Arabidopsis. We identify a cgb mutant that is hyper-susceptible to the pathogen Pseudomonas syringae. CGB encodes ROL5, a homolog of yeast NCS6 required for tRNA thiolation. ROL5 physically interacts with CTU2, a homolog of yeast NCS2. Mutations in either ROL5 or CTU2 result in loss of tRNA thiolation. Further analyses reveal that both transcriptome and proteome reprogramming during immune responses are compromised in cgb. Notably, the translation of salicylic acid receptor NPR1 is reduced in cgb, resulting in compromised salicylic acid signaling. Our study not only reveals a regulatory mechanism for plant immunity but also uncovers an additional biological function of tRNA thiolation.
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Affiliation(s)
- Xueao Zheng
- Hubei Hongshan LaboratoryWuhanChina
- Zhengzhou Tobacco Research Institute of CNTCZhengzhouChina
- College of Life Science and Technology, Huazhong Agricultural UniversityWuhanChina
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern AgricultureShenzhenChina
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural SciencesShenzhenChina
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural UniversityShenzhenChina
| | - Hanchen Chen
- Hubei Hongshan LaboratoryWuhanChina
- College of Life Science and Technology, Huazhong Agricultural UniversityWuhanChina
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern AgricultureShenzhenChina
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural SciencesShenzhenChina
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural UniversityShenzhenChina
| | - Zhiping Deng
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Virology and Biotechnology, Zhejiang Academy of Agricultural SciencesHangzhouChina
| | - Yujing Wu
- Hubei Hongshan LaboratoryWuhanChina
- College of Life Science and Technology, Huazhong Agricultural UniversityWuhanChina
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern AgricultureShenzhenChina
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural SciencesShenzhenChina
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural UniversityShenzhenChina
| | - Linlin Zhong
- Key Laboratory of Horticultural Plant Biology, Ministry of Education, College of Horticulture and Forestry Sciences, Huazhong Agricultural UniversityWuhanChina
| | - Chong Wu
- Hubei Hongshan LaboratoryWuhanChina
- College of Life Science and Technology, Huazhong Agricultural UniversityWuhanChina
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern AgricultureShenzhenChina
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural SciencesShenzhenChina
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural UniversityShenzhenChina
| | - Xiaodan Yu
- Hubei Hongshan LaboratoryWuhanChina
- College of Life Science and Technology, Huazhong Agricultural UniversityWuhanChina
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern AgricultureShenzhenChina
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural SciencesShenzhenChina
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural UniversityShenzhenChina
| | - Qiansi Chen
- Zhengzhou Tobacco Research Institute of CNTCZhengzhouChina
| | - Shunping Yan
- Hubei Hongshan LaboratoryWuhanChina
- College of Life Science and Technology, Huazhong Agricultural UniversityWuhanChina
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern AgricultureShenzhenChina
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural SciencesShenzhenChina
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural UniversityShenzhenChina
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11
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Tang M, Bi H, Dong Z, Zeng L. [Abnormal transfer RNA epigenetic modifications and related impact on neurodegenerative diseases]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2024; 54:58-69. [PMID: 39608797 PMCID: PMC11956855 DOI: 10.3724/zdxbyxb-2024-0203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 11/11/2024] [Indexed: 11/30/2024]
Abstract
Neurodegenerative diseases are a heterogeneous group of neurological disorders characterized by progressive loss of neurons in the central or peripheral nervous system. Research on the pathogenesis and drug targets of these diseases still faces many challenges due to the complex etiology. In recent years, the role of epigenetic modifications in transfer RNA (tRNA) in neurodegenerative diseases has attracted widespread attention. The tRNA modifications are crucial for regulating codon recognition, maintaining molecular structural stability, and the generation of tRNA-derived fragments (tRFs). Recent studies have highlighted a close association between abnormal tRNA modifications and the pathogenesis of various neurodegenerative diseases, especially for abnormalities of elongator complex-dependent tRNA modification and methylation modification, which impact the translation process and tRFs levels. These changes regulate protein homeostasis and cellular stress responses, ultimately influencing the survival of neuronal cells. Moreover, significant changes in tRFs levels have been observed in neurodegenerative diseases, and specific tRFs show distinct effects on neurodegenerative diseases. This review aims to provide an overview of the physiological functions of tRNA epigenetic modifications and their regulatory mechanisms in neurodegenerative diseases, covering both classical functions such as codon recognition and non-classical functions such as tRFs biogenesis. Additionally, the potential of targeting tRNA modifications for therapeutic applications is discussed.
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Affiliation(s)
- Mingmin Tang
- School of Medicine, Hangzhou City University, Hangzhou 310015, China.
- Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
| | - Hongyun Bi
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
- School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zijing Dong
- School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Linghui Zeng
- School of Medicine, Hangzhou City University, Hangzhou 310015, China.
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12
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Zeng Y, Lovchykova A, Akiyama T, Liu C, Guo C, Jawahar VM, Sianto O, Calliari A, Prudencio M, Dickson DW, Petrucelli L, Gitler AD. TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.22.575730. [PMID: 38328059 PMCID: PMC10849503 DOI: 10.1101/2024.01.22.575730] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.
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Affiliation(s)
- Yi Zeng
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Tetsuya Akiyama
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Chang Liu
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Caiwei Guo
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Vidhya Maheswari Jawahar
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
| | - Odilia Sianto
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Anna Calliari
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
| | - Mercedes Prudencio
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
| | - Dennis W. Dickson
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
| | - Leonard Petrucelli
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA
| | - Aaron D. Gitler
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Chan Zuckerberg Biohub – San Francisco, San Francisco, CA, USA
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13
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Eck RJ, Stair JG, Kraemer BC, Liachko NF. Simple models to understand complex disease: 10 years of progress from Caenorhabditis elegans models of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Front Neurosci 2024; 17:1300705. [PMID: 38239833 PMCID: PMC10794587 DOI: 10.3389/fnins.2023.1300705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 11/28/2023] [Indexed: 01/22/2024] Open
Abstract
The nematode Caenorhabditis elegans are a powerful model system to study human disease, with numerous experimental advantages including significant genetic and cellular homology to vertebrate animals, a short lifespan, and tractable behavioral, molecular biology and imaging assays. Beginning with the identification of SOD1 as a genetic cause of amyotrophic lateral sclerosis (ALS), C. elegans have contributed to a deeper understanding of the mechanistic underpinnings of this devastating neurodegenerative disease. More recently this work has expanded to encompass models of other types of ALS and the related disease frontotemporal lobar degeneration (FTLD-TDP), including those characterized by mutation or accumulation of the proteins TDP-43, C9orf72, FUS, HnRNPA2B1, ALS2, DCTN1, CHCHD10, ELP3, TUBA4A, CAV1, UBQLN2, ATXN3, TIA1, KIF5A, VAPB, GRN, and RAB38. In this review we summarize these models and the progress and insights from the last ten years of using C. elegans to study the neurodegenerative diseases ALS and FTLD-TDP.
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Affiliation(s)
- Randall J. Eck
- Graduate Program in Neuroscience, University of Washington, Seattle, WA, United States
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Jade G. Stair
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
| | - Brian C. Kraemer
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
| | - Nicole F. Liachko
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
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14
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Dey B, Kumar A, Patel AB. Pathomechanistic Networks of Motor System Injury in Amyotrophic Lateral Sclerosis. Curr Neuropharmacol 2024; 22:1778-1806. [PMID: 37622689 PMCID: PMC11284732 DOI: 10.2174/1570159x21666230824091601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/25/2023] [Accepted: 06/06/2023] [Indexed: 08/26/2023] Open
Abstract
Amyotrophic Lateral Sclerosis (ALS) is the most common, adult-onset, progressive motor neurodegenerative disorder that results in death within 3 years of the clinical diagnosis. Due to the clinicopathological heterogeneity, any reliable biomarkers for diagnosis or prognosis of ALS have not been identified till date. Moreover, the only three clinically approved treatments are not uniformly effective in slowing the disease progression. Over the last 15 years, there has been a rapid advancement in research on the complex pathomechanistic landscape of ALS that has opened up new avenues for successful clinical translation of targeted therapeutics. Multiple studies suggest that the age-dependent interaction of risk-associated genes with environmental factors and endogenous modifiers is critical to the multi-step process of ALS pathogenesis. In this review, we provide an updated discussion on the dysregulated cross-talk between intracellular homeostasis processes, the unique molecular networks across selectively vulnerable cell types, and the multisystemic nature of ALS pathomechanisms. Importantly, this work highlights the alteration in epigenetic and epitranscriptomic landscape due to gene-environment interactions, which have been largely overlooked in the context of ALS pathology. Finally, we suggest that precision medicine research in ALS will be largely benefitted from the stratification of patient groups based on the clinical phenotype, onset and progression, genome, exposome, and metabolic identities.
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Affiliation(s)
- Bedaballi Dey
- CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad 500007, Telangana, India
- AcSIR-Academy of Scientific and Innovative Research, Ghaziabad 201002, Uttar Pradesh, India
| | - Arvind Kumar
- CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad 500007, Telangana, India
- AcSIR-Academy of Scientific and Innovative Research, Ghaziabad 201002, Uttar Pradesh, India
| | - Anant Bahadur Patel
- CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad 500007, Telangana, India
- AcSIR-Academy of Scientific and Innovative Research, Ghaziabad 201002, Uttar Pradesh, India
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15
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Pereira M, Ribeiro DR, Berg M, Tsai AP, Dong C, Nho K, Kaiser S, Moutinho M, Soares AR. Amyloid pathology reduces ELP3 expression and tRNA modifications leading to impaired proteostasis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166857. [PMID: 37640114 DOI: 10.1016/j.bbadis.2023.166857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/09/2023] [Accepted: 08/22/2023] [Indexed: 08/31/2023]
Abstract
Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by accumulation of β-amyloid aggregates and loss of proteostasis. Transfer RNA (tRNA) modifications play a crucial role in maintaining proteostasis, but their impact in AD remains unclear. Here, we report that expression of the tRNA modifying enzyme ELP3 is reduced in the brain of AD patients and amyloid mouse models and negatively correlates with amyloid plaque mean density. We further show that SH-SY5Y neuronal cells carrying the amyloidogenic Swedish familial AD mutation (SH-SWE) display reduced ELP3 levels, tRNA hypomodifications and proteostasis impairments when compared to cells not carrying the mutation (SH-WT). Additionally, exposing SH-WT cells to the secretome of SH-SWE cells led to reduced ELP3 expression, wobble uridine tRNA hypomodification, and increased protein aggregation. Importantly, correcting tRNA deficits due to ELP3 reduction reverted proteostasis impairments. These findings suggest that amyloid pathology dysregulates proteostasis by reducing ELP3 expression and tRNA modification levels, and that targeting tRNA modifications may be a potential therapeutic avenue to restore neuronal proteostasis in AD and preserve neuronal function.
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Affiliation(s)
- Marisa Pereira
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
| | - Diana R Ribeiro
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
| | - Maximilian Berg
- Institute of Pharmaceutical Chemistry, Goethe-University, Frankfurt, 60438, Germany
| | - Andy P Tsai
- Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Chuanpeng Dong
- Department of Medical and Molecular Genetics, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kwangsik Nho
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Stefanie Kaiser
- Institute of Pharmaceutical Chemistry, Goethe-University, Frankfurt, 60438, Germany
| | - Miguel Moutinho
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Ana R Soares
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal.
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16
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Teruel-Peña B, Gómez-Urquiza JL, Suleiman-Martos N, Prieto I, García-Cózar FJ, Ramírez-Sánchez M, Fernández-Martos C, Domínguez-Vías G. Systematic Review and Meta-Analyses of Aminopeptidases as Prognostic Biomarkers in Amyotrophic Lateral Sclerosis. Int J Mol Sci 2023; 24:ijms24087169. [PMID: 37108335 PMCID: PMC10138961 DOI: 10.3390/ijms24087169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord, brain stem, and cerebral cortex. Biomarkers for ALS are essential for disease detection and to provide information on potential therapeutic targets. Aminopeptidases catalyze the cleavage of amino acids from the amino terminus of protein or substrates such as neuropeptides. Since certain aminopeptidases are known to increase the risk of neurodegeneration, such mechanisms may reveal new targets to determine their association with ALS risk and their interest as a diagnostic biomarker. The authors performed a systematic review and meta-analyses of genome-wide association studies (GWASs) to identify reported aminopeptidases genetic loci associated with the risk of ALS. PubMed, Scopus, CINAHL, ISI Web of Science, ProQuest, LILACS, and Cochrane databases were searched to retrieve eligible studies in English or Spanish, published up to 27 January 2023. A total of 16 studies were included in this systematic review, where a series of aminopeptidases could be related to ALS and could be promising biomarkers (DPP1, DPP2, DPP4, LeuAP, pGluAP, and PSA/NPEPPS). The literature reported the association of single-nucleotide polymorphisms (SNPs: rs10260404 and rs17174381) with the risk of ALS. The genetic variation rs10260404 in the DPP6 gene was identified to be highly associated with ALS susceptibility, but meta-analyses of genotypes in five studies in a matched cohort of different ancestry (1873 cases and 1861 control subjects) showed no ALS risk association. Meta-analyses of eight studies for minor allele frequency (MAF) also found no ALS association for the "C" allele. The systematic review identified aminopeptidases as possible biomarkers. However, the meta-analyses for rs1060404 of DPP6 do not show a risk associated with ALS.
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Affiliation(s)
- Bárbara Teruel-Peña
- Department of Health Sciences, University of Jaén, 23071 Jaén, Spain
- Department of Physiology, Faculty of Health Sciences, Ceuta University of Granada, 51001 Ceuta, Spain
| | - José Luís Gómez-Urquiza
- Nursing Department, Faculty of Health Sciences, Ceuta University of Granada, 51001 Ceuta, Spain
| | - Nora Suleiman-Martos
- Nursing Department, Faculty of Health Sciences, University of Granada, 18071 Granada, Spain
| | - Isabel Prieto
- Department of Health Sciences, University of Jaén, 23071 Jaén, Spain
| | | | | | | | - Germán Domínguez-Vías
- Department of Physiology, Faculty of Health Sciences, Ceuta University of Granada, 51001 Ceuta, Spain
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17
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Jaciuk M, Scherf D, Kaszuba K, Gaik M, Rau A, Kościelniak A, Krutyhołowa R, Rawski M, Indyka P, Graziadei A, Chramiec-Głąbik A, Biela A, Dobosz D, Lin TY, Abbassi NEH, Hammermeister A, Rappsilber J, Kosinski J, Schaffrath R, Glatt S. Cryo-EM structure of the fully assembled Elongator complex. Nucleic Acids Res 2023; 51:2011-2032. [PMID: 36617428 PMCID: PMC10018365 DOI: 10.1093/nar/gkac1232] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/22/2022] [Accepted: 12/09/2022] [Indexed: 01/10/2023] Open
Abstract
Transfer RNA (tRNA) molecules are essential to decode messenger RNA codons during protein synthesis. All known tRNAs are heavily modified at multiple positions through post-transcriptional addition of chemical groups. Modifications in the tRNA anticodons are directly influencing ribosome decoding and dynamics during translation elongation and are crucial for maintaining proteome integrity. In eukaryotes, wobble uridines are modified by Elongator, a large and highly conserved macromolecular complex. Elongator consists of two subcomplexes, namely Elp123 containing the enzymatically active Elp3 subunit and the associated Elp456 hetero-hexamer. The structure of the fully assembled complex and the function of the Elp456 subcomplex have remained elusive. Here, we show the cryo-electron microscopy structure of yeast Elongator at an overall resolution of 4.3 Å. We validate the obtained structure by complementary mutational analyses in vitro and in vivo. In addition, we determined various structures of the murine Elongator complex, including the fully assembled mouse Elongator complex at 5.9 Å resolution. Our results confirm the structural conservation of Elongator and its intermediates among eukaryotes. Furthermore, we complement our analyses with the biochemical characterization of the assembled human Elongator. Our results provide the molecular basis for the assembly of Elongator and its tRNA modification activity in eukaryotes.
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Affiliation(s)
- Marcin Jaciuk
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
| | - David Scherf
- Institute for Biology, Department for Microbiology, University of Kassel, Kassel 34132, Germany
| | - Karol Kaszuba
- European Molecular Biology Laboratory Hamburg, Hamburg 22607, Germany
- Centre for Structural Systems Biology (CSSB), Hamburg 22607, Germany
| | - Monika Gaik
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
| | - Alexander Rau
- Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin 13355, Germany
| | - Anna Kościelniak
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
| | - Rościsław Krutyhołowa
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
| | - Michał Rawski
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
- National Synchrotron Radiation Centre SOLARIS, Jagiellonian University, Krakow 30-387, Poland
| | - Paulina Indyka
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
- National Synchrotron Radiation Centre SOLARIS, Jagiellonian University, Krakow 30-387, Poland
| | - Andrea Graziadei
- Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin 13355, Germany
| | | | - Anna Biela
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
| | - Dominika Dobosz
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
| | - Ting-Yu Lin
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
| | - Nour-el-Hana Abbassi
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw 02-091, Poland
| | - Alexander Hammermeister
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow 30-387, Poland
- Institute for Biology, Department for Microbiology, University of Kassel, Kassel 34132, Germany
| | - Juri Rappsilber
- Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin 13355, Germany
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK
| | - Jan Kosinski
- European Molecular Biology Laboratory Hamburg, Hamburg 22607, Germany
- Centre for Structural Systems Biology (CSSB), Hamburg 22607, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany
| | - Raffael Schaffrath
- Institute for Biology, Department for Microbiology, University of Kassel, Kassel 34132, Germany
| | - Sebastian Glatt
- To whom correspondence should be addressed. Tel: +48 12 664 6321; Fax: +48 12 664 6902;
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18
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Costello SM, Cheney AM, Waldum A, Tripet B, Cotrina-Vidal M, Kaufmann H, Norcliffe-Kaufmann L, Lefcort F, Copié V. A Comprehensive NMR Analysis of Serum and Fecal Metabolites in Familial Dysautonomia Patients Reveals Significant Metabolic Perturbations. Metabolites 2023; 13:metabo13030433. [PMID: 36984872 PMCID: PMC10057143 DOI: 10.3390/metabo13030433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/06/2023] [Accepted: 03/14/2023] [Indexed: 03/18/2023] Open
Abstract
Central metabolism has a profound impact on the clinical phenotypes and penetrance of neurological diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases, Amyotrophic Lateral Sclerosis (ALS) and Autism Spectrum Disorder (ASD). In contrast to the multifactorial origin of these neurological diseases, neurodevelopmental impairment and neurodegeneration in Familial Dysautonomia (FD) results from a single point mutation in the ELP1 gene. FD patients represent a well-defined population who can help us better understand the cellular networks underlying neurodegeneration, and how disease traits are affected by metabolic dysfunction, which in turn may contribute to dysregulation of the gut–brain axis of FD. Here, 1H NMR spectroscopy was employed to characterize the serum and fecal metabolomes of FD patients, and to assess similarities and differences in the polar metabolite profiles between FD patients and healthy relative controls. Findings from this work revealed noteworthy metabolic alterations reflected in energy (ATP) production, mitochondrial function, amino acid and nucleotide catabolism, neurosignaling molecules, and gut-microbial metabolism. These results provide further evidence for a close interconnection between metabolism, neurodegeneration, and gut microbiome dysbiosis in FD, and create an opportunity to explore whether metabolic interventions targeting the gut–brain–metabolism axis of FD could be used to redress or slow down the progressive neurodegeneration observed in FD patients.
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Affiliation(s)
- Stephanann M. Costello
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
| | - Alexandra M. Cheney
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
| | - Annie Waldum
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
| | - Brian Tripet
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
| | - Maria Cotrina-Vidal
- Department of Neurology, New York University School of Medicine, New York, NY 10017, USA
| | - Horacio Kaufmann
- Department of Neurology, New York University School of Medicine, New York, NY 10017, USA
| | | | - Frances Lefcort
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA
| | - Valérie Copié
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
- Correspondence: ; Tel.: +1-406-994-7244
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19
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A novel ELP1 mutation impairs the function of the Elongator complex and causes a severe neurodevelopmental phenotype. J Hum Genet 2023. [PMID: 36864284 DOI: 10.1038/s10038-023-01135-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
Abstract
BACKGROUND Neurodevelopmental disorders (NDDs) are heterogeneous, debilitating conditions that include motor and cognitive disability and social deficits. The genetic factors underlying the complex phenotype of NDDs remain to be elucidated. Accumulating evidence suggest that the Elongator complex plays a role in NDDs, given that patient-derived mutations in its ELP2, ELP3, ELP4 and ELP6 subunits have been associated with these disorders. Pathogenic variants in its largest subunit ELP1 have been previously found in familial dysautonomia and medulloblastoma, with no link to NDDs affecting primarily the central nervous system. METHODS Clinical investigation included patient history and physical, neurological and magnetic resonance imaging (MRI) examination. A novel homozygous likely pathogenic ELP1 variant was identified by whole-genome sequencing. Functional studies included in silico analysis of the mutated ELP1 in the context of the holo-complex, production and purification of the ELP1 harbouring the identified mutation and in vitro analyses using microscale thermophoresis for tRNA binding assay and acetyl-CoA hydrolysis assay. Patient fibroblasts were harvested for tRNA modification analysis using HPLC coupled to mass spectrometry. RESULTS We report a novel missense mutation in the ELP1 identified in two siblings with intellectual disability and global developmental delay. We show that the mutation perturbs the ability of ELP123 to bind tRNAs and compromises the function of the Elongator in vitro and in human cells. CONCLUSION Our study expands the mutational spectrum of ELP1 and its association with different neurodevelopmental conditions and provides a specific target for genetic counselling.
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Cheney AM, Costello SM, Pinkham NV, Waldum A, Broadaway SC, Cotrina-Vidal M, Mergy M, Tripet B, Kominsky DJ, Grifka-Walk HM, Kaufmann H, Norcliffe-Kaufmann L, Peach JT, Bothner B, Lefcort F, Copié V, Walk ST. Gut microbiome dysbiosis drives metabolic dysfunction in Familial dysautonomia. Nat Commun 2023; 14:218. [PMID: 36639365 PMCID: PMC9839693 DOI: 10.1038/s41467-023-35787-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 12/18/2022] [Indexed: 01/15/2023] Open
Abstract
Familial dysautonomia (FD) is a rare genetic neurologic disorder caused by impaired neuronal development and progressive degeneration of both the peripheral and central nervous systems. FD is monogenic, with >99.4% of patients sharing an identical point mutation in the elongator acetyltransferase complex subunit 1 (ELP1) gene, providing a relatively simple genetic background in which to identify modifiable factors that influence pathology. Gastrointestinal symptoms and metabolic deficits are common among FD patients, which supports the hypothesis that the gut microbiome and metabolome are altered and dysfunctional compared to healthy individuals. Here we show significant differences in gut microbiome composition (16 S rRNA gene sequencing of stool samples) and NMR-based stool and serum metabolomes between a cohort of FD patients (~14% of patients worldwide) and their cohabitating, healthy relatives. We show that key observations in human subjects are recapitulated in a neuron-specific Elp1-deficient mouse model, and that cohousing mutant and littermate control mice ameliorates gut microbiome dysbiosis, improves deficits in gut transit, and reduces disease severity. Our results provide evidence that neurologic deficits in FD alter the structure and function of the gut microbiome, which shifts overall host metabolism to perpetuate further neurodegeneration.
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Affiliation(s)
- Alexandra M Cheney
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA
| | - Stephanann M Costello
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA
| | - Nicholas V Pinkham
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, USA
| | - Annie Waldum
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA
| | - Susan C Broadaway
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, USA
| | - Maria Cotrina-Vidal
- Department of Neurology, New York University School of Medicine, New York, NY, USA
| | - Marc Mergy
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, USA
| | - Brian Tripet
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA
| | - Douglas J Kominsky
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, USA
| | - Heather M Grifka-Walk
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, USA
| | - Horacio Kaufmann
- Department of Neurology, New York University School of Medicine, New York, NY, USA
| | | | - Jesse T Peach
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA
| | - Brian Bothner
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA
| | - Frances Lefcort
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, USA.
| | - Valérie Copié
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA.
| | - Seth T Walk
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, USA.
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Kabir F, Atkinson R, Cook AL, Phipps AJ, King AE. The role of altered protein acetylation in neurodegenerative disease. Front Aging Neurosci 2023; 14:1025473. [PMID: 36688174 PMCID: PMC9845957 DOI: 10.3389/fnagi.2022.1025473] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/03/2022] [Indexed: 01/06/2023] Open
Abstract
Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.
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22
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Muzio L, Ghirelli A, Agosta F, Martino G. Novel therapeutic approaches for motor neuron disease. HANDBOOK OF CLINICAL NEUROLOGY 2023; 196:523-537. [PMID: 37620088 DOI: 10.1016/b978-0-323-98817-9.00027-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to the neurodegeneration and death of upper and lower motor neurons (MNs). Although MNs are the main cells involved in the process of neurodegeneration, a growing body of evidence points toward other cell types as concurrent to disease initiation and propagation. Given the current absence of effective therapies, the quest for other therapeutic targets remains open and still challenges the scientific community. Both neuronal and extra-neuronal mechanisms of cellular stress and damage have been studied and have posed the basis for the development of novel therapies that have been investigated on both animal models and humans. In this chapter, a thorough review of the main mechanisms of cellular damage and the respective therapeutic attempts targeting them is reported. The main areas covered include neuroinflammation, protein aggregation, RNA metabolism, and oxidative stress.
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Affiliation(s)
- Luca Muzio
- San Raffaele Scientific Institute, Division of Neuroscience, InsPE, Milan, Italy
| | - Alma Ghirelli
- San Raffaele Scientific Institute, Division of Neuroscience, InsPE, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Federica Agosta
- San Raffaele Scientific Institute, Division of Neuroscience, InsPE, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Gianvito Martino
- San Raffaele Scientific Institute, Division of Neuroscience, InsPE, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
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23
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Zhang L, Liu Y, Lu Y, Wang G. Targeting epigenetics as a promising therapeutic strategy for treatment of neurodegenerative diseases. Biochem Pharmacol 2022; 206:115295. [DOI: 10.1016/j.bcp.2022.115295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022]
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24
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Qi Z, Li J, Li M, Du X, Zhang L, Wang S, Xu B, Liu W, Xu Z, Deng Y. The Essential Role of Epigenetic Modifications in Neurodegenerative Diseases with Dyskinesia. Cell Mol Neurobiol 2022; 42:2459-2472. [PMID: 34383231 PMCID: PMC11421617 DOI: 10.1007/s10571-021-01133-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 07/18/2021] [Indexed: 12/20/2022]
Abstract
Epigenetics play an essential role in the occurrence and improvement of many diseases. Evidence shows that epigenetic modifications are crucial to the regulation of gene expression. DNA methylation is closely linked to embryonic development in mammalian. In recent years, epigenetic drugs have shown unexpected therapeutic effects on neurological diseases, leading to the study of the epigenetic mechanism in neurodegenerative diseases. Unlike genetics, epigenetics modify the genome without changing the DNA sequence. Research shows that epigenetics is involved in all aspects of neurodegenerative diseases. The study of epigenetic will provide valuable insights into the molecular mechanism of neurodegenerative diseases, which may lead to new treatments and diagnoses. This article reviews the role of epigenetic modifications neurodegenerative diseases with dyskinesia, and discusses the therapeutic potential of epigenetic drugs in neurodegenerative diseases.
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Affiliation(s)
- Zhipeng Qi
- Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Jiashuo Li
- Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Minghui Li
- Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Xianchao Du
- Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Lei Zhang
- Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Shuang Wang
- Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Bin Xu
- Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Wei Liu
- Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Zhaofa Xu
- Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Yu Deng
- Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China.
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Wagner A, Schosserer M. The epitranscriptome in ageing and stress resistance: A systematic review. Ageing Res Rev 2022; 81:101700. [PMID: 35908668 DOI: 10.1016/j.arr.2022.101700] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/15/2022] [Accepted: 07/25/2022] [Indexed: 01/31/2023]
Abstract
Modifications of RNA, collectively called the "epitranscriptome", might provide novel biomarkers and innovative targets for interventions in geroscience but are just beginning to be studied in the context of ageing and stress resistance. RNA modifications modulate gene expression by affecting translation initiation and speed, miRNA binding, RNA stability, and RNA degradation. Nonetheless, the precise underlying molecular mechanisms and physiological consequences of most alterations of the epitranscriptome are still only poorly understood. We here systematically review different types of modifications of rRNA, tRNA and mRNA, the methodology to analyze them, current challenges in the field, and human disease associations. Furthermore, we compiled evidence for a connection between individual enzymes, which install RNA modifications, and lifespan in yeast, worm and fly. We also included resistance to different stressors and competitive fitness as search criteria for genes potentially relevant to ageing. Promising candidates identified by this approach include RCM1/NSUN5, RRP8, and F33A8.4/ZCCHC4 that introduce base methylations in rRNA, the methyltransferases DNMT2 and TRM9/ALKBH8, as well as factors involved in the thiolation or A to I editing in tRNA, and finally the m6A machinery for mRNA.
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Affiliation(s)
- Anja Wagner
- Institute of Molecular Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Markus Schosserer
- Institute of Molecular Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria; Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria.
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26
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TFEB acetylation promotes lysosome biogenesis and ameliorates Alzheimer's disease-relevant phenotypes in mice. J Biol Chem 2022; 298:102649. [PMID: 36441024 PMCID: PMC9694136 DOI: 10.1016/j.jbc.2022.102649] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 11/24/2022] Open
Abstract
Lysosomes are one of the major centers for regulating cargo degradation and protein quality control. Transcription factor EB (TFEB)-promoted lysosome biogenesis enhances lysosome-mediated degradation and alleviates neurodegenerative diseases, but the mechanisms underlying TFEB modification and activation are still poorly understood. Here, we report essential roles of TFEB acetylation in TFEB nuclear translocation and lysosome biogenesis, which are independent of TFEB dephosphorylation. By screening small molecules, we find that Trichostatin A (TSA), the pan-inhibitor of histone deacetylases (HDACs), promotes nuclear translocation of TFEB. TSA enhances the staining of cells by LysoTracker Red and increases the expression of lysosomal and autophagic genes. We identify four novel acetylated lysine residues in TFEB, which are important for TFEB nuclear translocation and lysosome biogenesis. We show that TFEB acetylation is regulated by HDACs (HDAC5, HDAC6, and HDAC9) and lysine acetyltransferases (KATs), including ELP3, CREBBP, and HAT1. During TSA-induced cytosol-to-nucleus translocation of TFEB, acetylation is independent of TFEB dephosphorylation, since the mTORC1- or GSK3β-related phosphorylation sites on TFEB are still phosphorylated. Administration of TSA to APP/PS1 mice increases the expression of lysosomal and autophagic genes in mouse brains and also improves memory. Accordingly, the β-amyloid plaque burden is decreased. These results show that the acetylation of TFEB, as a novel mechanism of TFEB activation, promotes lysosome biogenesis and alleviates the pathogenesis of Alzheimer's disease. Our results also suggest that HDAC inhibition can promote lysosome biogenesis, and this may be a potential therapeutic approach for the treatment of neurodegenerative diseases and disorders related to HDAC hyperactivation.
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27
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Hu L, Mao S, Lin L, Bai G, Liu B, Mao J. Stress granules in the spinal muscular atrophy and amyotrophic lateral sclerosis: The correlation and promising therapy. Neurobiol Dis 2022; 170:105749. [PMID: 35568100 DOI: 10.1016/j.nbd.2022.105749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 03/27/2022] [Accepted: 05/05/2022] [Indexed: 10/18/2022] Open
Abstract
Increasing genetic and biochemical evidence has broadened our view of the pathomechanisms that lead to Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS), two fatal neurodegenerative diseases with similar symptoms and causes. Stress granules are dynamic cytosolic storage hubs for mRNAs in response to stress exposures, that are evolutionarily conserved cytoplasmic RNA granules in somatic cells. A lot of previous studies have shown that the impaired stress granules are crucial events in SMA/ALS pathogenesis. In this review, we described the key stress granules related RNA binding proteins (SMN, TDP-43, and FUS) involved in SMA/ALS, summarized the reported mutations in these RNA binding proteins involved in SMA/ALS pathogenesis, and discussed the mechanisms through which stress granules dynamics participate in the diseases. Meanwhile, we described the applications and limitation of current therapies targeting SMA/ALS. We futher proposed the promising targets on stress granules in the future therapeutic interventions of SMA/ALS.
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Affiliation(s)
- LiDan Hu
- the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
| | - Shanshan Mao
- the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Li Lin
- the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Guannan Bai
- the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Bingjie Liu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Jianhua Mao
- the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
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Blaze J, Akbarian S. The tRNA regulome in neurodevelopmental and neuropsychiatric disease. Mol Psychiatry 2022; 27:3204-3213. [PMID: 35505091 PMCID: PMC9630165 DOI: 10.1038/s41380-022-01585-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/11/2022] [Accepted: 04/13/2022] [Indexed: 12/14/2022]
Abstract
Transfer (t)RNAs are 70-90 nucleotide small RNAs highly regulated by 43 different types of epitranscriptomic modifications and requiring aminoacylation ('charging') for mRNA decoding and protein synthesis. Smaller cleavage products of mature tRNAs, or tRNA fragments, have been linked to a broad variety of noncanonical functions, including translational inhibition and modulation of the immune response. Traditionally, knowledge about tRNA regulation in brain is derived from phenotypic exploration of monogenic neurodevelopmental and neurodegenerative diseases associated with rare mutations in tRNA modification genes. More recent studies point to the previously unrecognized potential of the tRNA regulome to affect memory, synaptic plasticity, and affective states. For example, in mature cortical neurons, cytosine methylation sensitivity of the glycine tRNA family (tRNAGly) is coupled to glycine biosynthesis and codon-specific alterations in ribosomal translation together with robust changes in cognition and depression-related behaviors. In this Review, we will discuss the emerging knowledge of the neuronal tRNA landscape, with a focus on epitranscriptomic tRNA modifications and downstream molecular pathways affected by alterations in tRNA expression, charging levels, and cleavage while mechanistically linking these pathways to neuropsychiatric disease and provide insight into future areas of study for this field.
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Affiliation(s)
- Jennifer Blaze
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. .,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Schahram Akbarian
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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29
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Walters J, Walters C, Cameron B, George L. Elongator regulates the melanocortin satiety pathway. Biochem Biophys Res Commun 2022; 613:73-80. [PMID: 35537288 PMCID: PMC9156574 DOI: 10.1016/j.bbrc.2022.04.128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 04/27/2022] [Indexed: 11/19/2022]
Abstract
This study investigates the function of Elp1 and Elongator in the pituitary gland. Two conditional knockout models were generated where Elp1 was selectively deleted in either somatotropes of the anterior pituitary or Pomc-expressing cells of the anterior and intermediate pituitary. Although loss of Elp1 in somatotropes did not significantly impact murine growth or development, its loss in Pomc-expressing cells resulted in dramatically reduced levels of α-MSH, hyperphagia and obesity. This report provides the first evidence that Elongator plays an essential role in regulating the melanocortin satiety pathway.
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Affiliation(s)
- Joseph Walters
- Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, 59101, USA; Pacific Northwest University of Health Sciences, Yakima, WA, 98901, USA
| | - Cody Walters
- Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, 59101, USA; UC Davis School of Medicine, Sacramento, CA, 59817, USA
| | - BreAnna Cameron
- Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, 59101, USA
| | - Lynn George
- Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, 59101, USA.
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30
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Gaik M, Kojic M, Stegeman MR, Öncü‐Öner T, Kościelniak A, Jones A, Mohamed A, Chau PYS, Sharmin S, Chramiec‐Głąbik A, Indyka P, Rawski M, Biela A, Dobosz D, Millar A, Chau V, Ünalp A, Piper M, Bellingham MC, Eichler EE, Nickerson DA, Güleryüz H, Abbassi NEH, Jazgar K, Davis MJ, Mercimek‐Andrews S, Cingöz S, Wainwright BJ, Glatt S. Functional divergence of the two Elongator subcomplexes during neurodevelopment. EMBO Mol Med 2022; 14:e15608. [PMID: 35698786 PMCID: PMC9260213 DOI: 10.15252/emmm.202115608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 12/11/2022] Open
Abstract
The highly conserved Elongator complex is a translational regulator that plays a critical role in neurodevelopment, neurological diseases, and brain tumors. Numerous clinically relevant variants have been reported in the catalytic Elp123 subcomplex, while no missense mutations in the accessory subcomplex Elp456 have been described. Here, we identify ELP4 and ELP6 variants in patients with developmental delay, epilepsy, intellectual disability, and motor dysfunction. We determine the structures of human and murine Elp456 subcomplexes and locate the mutated residues. We show that patient-derived mutations in Elp456 affect the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modeling the pathogenic variants in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity, and neurological defects. Foremost, our data indicate previously unrecognized differences of the Elp123 and Elp456 subcomplexes for individual tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.
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31
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Morini E, Gao D, Logan EM, Salani M, Krauson AJ, Chekuri A, Chen YT, Ragavendran A, Chakravarty P, Erdin S, Stortchevoi A, Svejstrup JQ, Talkowski ME, Slaugenhaupt SA. Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage. J Genet Genomics 2022; 49:654-665. [PMID: 34896608 PMCID: PMC9254147 DOI: 10.1016/j.jgg.2021.11.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 10/27/2021] [Accepted: 11/04/2021] [Indexed: 01/21/2023]
Abstract
Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1 (ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse (Elp1-/-) and observed that human ELP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression.
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Affiliation(s)
- Elisabetta Morini
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA
| | - Dadi Gao
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Emily M Logan
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
| | - Monica Salani
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
| | - Aram J Krauson
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
| | - Anil Chekuri
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA
| | - Yei-Tsung Chen
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taiwan
| | - Ashok Ragavendran
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Probir Chakravarty
- Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK
| | - Serkan Erdin
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Alexei Stortchevoi
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Jesper Q Svejstrup
- Mechanisms of Transcription Laboratory, The Francis Crick Institute, London, UK; Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - Michael E Talkowski
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Susan A Slaugenhaupt
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.
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The pathogenesis of amyotrophic lateral sclerosis: Mitochondrial dysfunction, protein misfolding and epigenetics. Brain Res 2022; 1786:147904. [PMID: 35390335 DOI: 10.1016/j.brainres.2022.147904] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 03/24/2022] [Accepted: 04/01/2022] [Indexed: 12/13/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with multiple complex mechanisms involved. Among them, mitochondrial dysfunction plays an important role in ALS. Multiple studies have shown that mitochondria are closely associated with reactive oxygen species production and oxidative stress and exhibit different functional states in different genetic backgrounds. In this review we explored the roles of Ca2+, autophagy, mitochondrial quality control in the regulation of mitochondrial homeostasis and their relationship with ALS. In addition, we also summarized and analyzed the roles of protein misfolding and abnormal aggregation in the pathogenesis of ALS. Moreover, we also discussed how epigenetic mechanisms such as DNA methylation and protein post-translational modification affect initiation and progression of ALS. Nevertheless, existing events still cannot fully explain the pathogenesis of ALS at present, more studies are required to explore pathological mechanisms of ALS.
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Dalwadi U, Mannar D, Zierhut F, Yip CK. Biochemical and Structural Characterization of Human Core Elongator and Its Subassemblies. ACS OMEGA 2022; 7:3424-3433. [PMID: 35128251 PMCID: PMC8811885 DOI: 10.1021/acsomega.1c05719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/31/2021] [Indexed: 06/14/2023]
Abstract
Conserved from yeast to humans and composed of six core subunits (Elp1-Elp6), Elongator is a multiprotein complex that catalyzes the modification of the anticodon loop of transfer RNAs (tRNAs) and in turn regulates messenger RNA decoding efficiency. Previous studies showed that yeast Elongator consists of two subassemblies (yElp1/2/3 and yElp4/5/6) and adopts an asymmetric overall architecture. Yet, much less is known about the structural properties of the orthologous human Elongator. Furthermore, the order in which the different Elongator subunits come together to form the full assembly as well as how they coordinate with one another to catalyze tRNA modification is not fully understood. Here, we purified recombinant human Elongator subunits and subassemblies and examined them by single-particle electron microscopy. We found that the human Elongator complex is assembled from two subcomplexes that share similar overall morphologies as their yeast counterparts. Complementary co-purification and pulldown assays revealed that the scaffolding subunit human ELP1 (hELP1) has stabilizing effects on the human ELP3 catalytic subunit. Furthermore, the peripheral hELP2 subunit appears to enhance the integrity and substrate-binding ability of the dimeric hELP1/2/3. Lastly, we found that hELP4/5/6 is recruited to hELP1/2/3 via hELP3. Collectively, our work generated insights into the assembly process of core human Elongator and the coordination of different subunits within this complex.
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Zhou JB, Wang ED, Zhou XL. Modifications of the human tRNA anticodon loop and their associations with genetic diseases. Cell Mol Life Sci 2021; 78:7087-7105. [PMID: 34605973 PMCID: PMC11071707 DOI: 10.1007/s00018-021-03948-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/07/2021] [Accepted: 09/21/2021] [Indexed: 12/11/2022]
Abstract
Transfer RNAs (tRNAs) harbor the most diverse posttranscriptional modifications. Among such modifications, those in the anticodon loop, either on nucleosides or base groups, compose over half of the identified posttranscriptional modifications. The derivatives of modified nucleotides and the crosstalk of different chemical modifications further add to the structural and functional complexity of tRNAs. These modifications play critical roles in maintaining anticodon loop conformation, wobble base pairing, efficient aminoacylation, and translation speed and fidelity as well as mediating various responses to different stress conditions. Posttranscriptional modifications of tRNA are catalyzed mainly by enzymes and/or cofactors encoded by nuclear genes, whose mutations are firmly connected with diverse human diseases involving genetic nervous system disorders and/or the onset of multisystem failure. In this review, we summarize recent studies about the mechanisms of tRNA modifications occurring at tRNA anticodon loops. In addition, the pathogenesis of related disease-causing mutations at these genes is briefly described.
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Affiliation(s)
- Jing-Bo Zhou
- State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - En-Duo Wang
- State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
- School of Life Science and Technology, ShanghaiTech University, 93 Middle Huaxia Road, Shanghai, 201210, China.
| | - Xiao-Long Zhou
- State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
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Das AS, Alfonzo JD, Accornero F. The importance of RNA modifications: From cells to muscle physiology. WILEY INTERDISCIPLINARY REVIEWS-RNA 2021; 13:e1700. [PMID: 34664402 DOI: 10.1002/wrna.1700] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/30/2021] [Accepted: 09/27/2021] [Indexed: 12/25/2022]
Abstract
Naturally occurring post-transcriptional chemical modifications serve critical roles in impacting RNA structure and function. More directly, modifications may affect RNA stability, intracellular transport, translational efficiency, and fidelity. The combination of effects caused by modifications are ultimately linked to gene expression regulation at a genome-wide scale. The latter is especially true in systems that undergo rapid metabolic and or translational remodeling in response to external stimuli, such as the presence of stressors, but beyond that, modifications may also affect cell homeostasis. Although examples of the importance of RNA modifications in translation are accumulating rapidly, still what these contribute to the function of complex physiological systems such as muscle is only recently emerging. In the present review, we will introduce key information on various modifications and highlight connections between those and cellular malfunctions. In passing, we will describe well-documented roles for modifications in the nervous system and use this information as a stepping stone to emphasize a glaring paucity of knowledge on the role of RNA modifications in heart and skeletal muscle, with particular emphasis on mitochondrial function in those systems. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > RNA Editing and Modification.
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Affiliation(s)
- Anindhya Sundar Das
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA.,The Center for RNA Biology, The Ohio State University, Columbus, Ohio, USA
| | - Juan D Alfonzo
- The Center for RNA Biology, The Ohio State University, Columbus, Ohio, USA.,Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
| | - Federica Accornero
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA.,The Center for RNA Biology, The Ohio State University, Columbus, Ohio, USA
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36
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ATP-citrate lyase promotes axonal transport across species. Nat Commun 2021; 12:5878. [PMID: 34620845 PMCID: PMC8497606 DOI: 10.1038/s41467-021-25786-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 08/24/2021] [Indexed: 01/22/2023] Open
Abstract
Microtubule (MT)-based transport is an evolutionary conserved process finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, primarily catalyzed by a vesicular pool of α-tubulin N-acetyltransferase 1 (Atat1), promotes the recruitment and processivity of molecular motors along MT tracks. However, the mechanism that controls Atat1 activity remains poorly understood. Here, we show that ATP-citrate lyase (Acly) is enriched in vesicles and provide Acetyl-Coenzyme-A (Acetyl-CoA) to Atat1. In addition, we showed that Acly expression is reduced upon loss of Elongator activity, further connecting Elongator to Atat1 in a pathway regulating α-tubulin acetylation and MT-dependent transport in projection neurons, across species. Remarkably, comparable defects occur in fibroblasts from Familial Dysautonomia (FD) patients bearing an autosomal recessive mutation in the gene coding for the Elongator subunit ELP1. Our data may thus shine light on the pathophysiological mechanisms underlying FD. Microtubule tracks are important for the transport of molecules within axons. Here, the authors show that ATAT1, the enzyme responsible for acetylating a-tubulin, receives acetyl groups from ATP citrate lyase whose stability is regulated by Elongator, a protein mutated in the neuronal disease Familial dysautonomia.
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Abstract
Neuroepigenetics, a new branch of epigenetics, plays an important role in the regulation of gene expression. Neuroepigenetics is associated with holistic neuronal function and helps in formation and maintenance of memory and learning processes. This includes neurodevelopment and neurodegenerative defects in which histone modification enzymes appear to play a crucial role. These modifications, carried out by acetyltransferases and deacetylases, regulate biologic and cellular processes such as apoptosis and autophagy, inflammatory response, mitochondrial dysfunction, cell-cycle progression and oxidative stress. Alterations in acetylation status of histone as well as non-histone substrates lead to transcriptional deregulation. Histone deacetylase decreases acetylation status and causes transcriptional repression of regulatory genes involved in neural plasticity, synaptogenesis, synaptic and neural plasticity, cognition and memory, and neural differentiation. Transcriptional deactivation in the brain results in development of neurodevelopmental and neurodegenerative disorders. Mounting evidence implicates histone deacetylase inhibitors as potential therapeutic targets to combat neurologic disorders. Recent studies have targeted naturally-occurring biomolecules and micro-RNAs to improve cognitive defects and memory. Multi-target drug ligands targeting HDAC have been developed and used in cell-culture and animal-models of neurologic disorders to ameliorate synaptic and cognitive dysfunction. Herein, we focus on the implications of histone deacetylase enzymes in neuropathology, their regulation of brain function and plausible involvement in the pathogenesis of neurologic defects.
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Sarkar A, Gasperi W, Begley U, Nevins S, Huber SM, Dedon PC, Begley TJ. Detecting the epitranscriptome. WILEY INTERDISCIPLINARY REVIEWS-RNA 2021; 12:e1663. [PMID: 33987958 DOI: 10.1002/wrna.1663] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 11/09/2022]
Abstract
RNA modifications and their corresponding epitranscriptomic writer and eraser enzymes regulate gene expression. Altered RNA modification levels, dysregulated writers, and sequence changes that disrupt epitranscriptomic marks have been linked to mitochondrial and neurological diseases, cancer, and multifactorial disorders. The detection of epitranscriptomics marks is challenging, but different next generation sequencing (NGS)-based and mass spectrometry-based approaches have been used to identify and quantitate the levels of individual and groups of RNA modifications. NGS and mass spectrometry-based approaches have been coupled with chemical, antibody or enzymatic methodologies to identify modifications in most RNA species, mapped sequence contexts and demonstrated the dynamics of specific RNA modifications, as well as the collective epitranscriptome. While epitranscriptomic analysis is currently limited to basic research applications, specific approaches for the detection of individual RNA modifications and the epitranscriptome have potential biomarker applications in detecting human conditions and diseases. This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Processing > tRNA Processing RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Anwesha Sarkar
- Department of Biological Sciences, University at Albany, Albany, New York, USA.,The RNA Institute, University at Albany, Albany, New York, USA
| | - William Gasperi
- Department of Biological Sciences, University at Albany, Albany, New York, USA.,The RNA Institute, University at Albany, Albany, New York, USA
| | - Ulrike Begley
- Department of Biological Sciences, University at Albany, Albany, New York, USA.,The RNA Institute, University at Albany, Albany, New York, USA
| | - Steven Nevins
- Nanoscale Science Constellation, SUNY Polytechnic Institute, Albany, New York, USA
| | | | - Peter C Dedon
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.,Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore
| | - Thomas J Begley
- Department of Biological Sciences, University at Albany, Albany, New York, USA.,The RNA Institute, University at Albany, Albany, New York, USA
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39
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Iron in Translation: From the Beginning to the End. Microorganisms 2021; 9:microorganisms9051058. [PMID: 34068342 PMCID: PMC8153317 DOI: 10.3390/microorganisms9051058] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/10/2021] [Accepted: 05/11/2021] [Indexed: 12/16/2022] Open
Abstract
Iron is an essential element for all eukaryotes, since it acts as a cofactor for many enzymes involved in basic cellular functions, including translation. While the mammalian iron-regulatory protein/iron-responsive element (IRP/IRE) system arose as one of the first examples of translational regulation in higher eukaryotes, little is known about the contribution of iron itself to the different stages of eukaryotic translation. In the yeast Saccharomyces cerevisiae, iron deficiency provokes a global impairment of translation at the initiation step, which is mediated by the Gcn2-eIF2α pathway, while the post-transcriptional regulator Cth2 specifically represses the translation of a subgroup of iron-related transcripts. In addition, several steps of the translation process depend on iron-containing enzymes, including particular modifications of translation elongation factors and transfer RNAs (tRNAs), and translation termination by the ATP-binding cassette family member Rli1 (ABCE1 in humans) and the prolyl hydroxylase Tpa1. The influence of these modifications and their correlation with codon bias in the dynamic control of protein biosynthesis, mainly in response to stress, is emerging as an interesting focus of research. Taking S. cerevisiae as a model, we hereby discuss the relevance of iron in the control of global and specific translation steps.
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Kojic M, Gawda T, Gaik M, Begg A, Salerno-Kochan A, Kurniawan ND, Jones A, Drożdżyk K, Kościelniak A, Chramiec-Głąbik A, Hediyeh-Zadeh S, Kasherman M, Shim WJ, Sinniah E, Genovesi LA, Abrahamsen RK, Fenger CD, Madsen CG, Cohen JS, Fatemi A, Stark Z, Lunke S, Lee J, Hansen JK, Boxill MF, Keren B, Marey I, Saenz MS, Brown K, Alexander SA, Mureev S, Batzilla A, Davis MJ, Piper M, Bodén M, Burne THJ, Palpant NJ, Møller RS, Glatt S, Wainwright BJ. Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype. Nat Commun 2021; 12:2678. [PMID: 33976153 PMCID: PMC8113450 DOI: 10.1038/s41467-021-22888-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 03/24/2021] [Indexed: 02/03/2023] Open
Abstract
Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.
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Affiliation(s)
- Marija Kojic
- The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Tomasz Gawda
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Monika Gaik
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Alexander Begg
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Anna Salerno-Kochan
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
- Postgraduate School of Molecular Medicine, Warsaw, Poland
| | - Nyoman D Kurniawan
- Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia
| | - Alun Jones
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Katarzyna Drożdżyk
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | - Anna Kościelniak
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
| | | | - Soroor Hediyeh-Zadeh
- Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
| | - Maria Kasherman
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
| | - Woo Jun Shim
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Enakshi Sinniah
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Laura A Genovesi
- The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Rannvá K Abrahamsen
- Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark
| | - Christina D Fenger
- Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark
| | - Camilla G Madsen
- Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark
| | - Julie S Cohen
- Department of Neurology and Developmental Medicine, Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ali Fatemi
- Department of Neurology and Developmental Medicine, Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zornitza Stark
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia
- Australian Genomics Health Alliance, Parkville, VIC, Australia
| | - Sebastian Lunke
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia
- Australian Genomics Health Alliance, Parkville, VIC, Australia
- The University of Melbourne, Melbourne, VIC, Australia
| | - Joy Lee
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia
- Department of Metabolic Medicine, Royal Children's Hospital, Parkville, VIC, Australia
| | - Jonas K Hansen
- Department of Paediatrics, Regional Hospital Viborg, Viborg, Denmark
| | - Martin F Boxill
- Department of Paediatrics, Regional Hospital Viborg, Viborg, Denmark
| | - Boris Keren
- Department of Genetics, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | - Isabelle Marey
- Department of Genetics, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | - Margarita S Saenz
- The University of Colorado Anschutz, Children's Hospital Colorado, Aurora, CO, USA
| | - Kathleen Brown
- The University of Colorado Anschutz, Children's Hospital Colorado, Aurora, CO, USA
| | - Suzanne A Alexander
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
- Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Brisbane, QLD, Australia
| | - Sergey Mureev
- CSIRO-QUT Synthetic Biology Alliance, Centre for Tropical Crops and Bio-commodities, Queensland University of Technology, Brisbane, QLD, Australia
| | - Alina Batzilla
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- The Ruprecht Karl University of Heidelberg, Heidelberg, Germany
| | - Melissa J Davis
- Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
- Department of Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
| | - Michael Piper
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
| | - Mikael Bodén
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Thomas H J Burne
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
- Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Brisbane, QLD, Australia
| | - Nathan J Palpant
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Rikke S Møller
- Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark
- Department for Regional Health Research, The University of Southern Denmark, Odense, Denmark
| | - Sebastian Glatt
- Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
| | - Brandon J Wainwright
- The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia.
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
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Sanchez Caballero L, Gorgogietas V, Arroyo MN, Igoillo-Esteve M. Molecular mechanisms of β-cell dysfunction and death in monogenic forms of diabetes. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:139-256. [PMID: 33832649 DOI: 10.1016/bs.ircmb.2021.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Monogenetic forms of diabetes represent 1%-5% of all diabetes cases and are caused by mutations in a single gene. These mutations, that affect genes involved in pancreatic β-cell development, function and survival, or insulin regulation, may be dominant or recessive, inherited or de novo. Most patients with monogenic diabetes are very commonly misdiagnosed as having type 1 or type 2 diabetes. The severity of their symptoms depends on the nature of the mutation, the function of the affected gene and, in some cases, the influence of additional genetic or environmental factors that modulate severity and penetrance. In some patients, diabetes is accompanied by other syndromic features such as deafness, blindness, microcephaly, liver and intestinal defects, among others. The age of diabetes onset may also vary from neonatal until early adulthood manifestations. Since the different mutations result in diverse clinical presentations, patients usually need different treatments that range from just diet and exercise, to the requirement of exogenous insulin or other hypoglycemic drugs, e.g., sulfonylureas or glucagon-like peptide 1 analogs to control their glycemia. As a consequence, awareness and correct diagnosis are crucial for the proper management and treatment of monogenic diabetes patients. In this chapter, we describe mutations causing different monogenic forms of diabetes associated with inadequate pancreas development or impaired β-cell function and survival, and discuss the molecular mechanisms involved in β-cell demise.
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Affiliation(s)
- Laura Sanchez Caballero
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Vyron Gorgogietas
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Maria Nicol Arroyo
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Mariana Igoillo-Esteve
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/.
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The expanding world of tRNA modifications and their disease relevance. Nat Rev Mol Cell Biol 2021; 22:375-392. [PMID: 33658722 DOI: 10.1038/s41580-021-00342-0] [Citation(s) in RCA: 409] [Impact Index Per Article: 102.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2021] [Indexed: 02/08/2023]
Abstract
Transfer RNA (tRNA) is an adapter molecule that links a specific codon in mRNA with its corresponding amino acid during protein synthesis. tRNAs are enzymatically modified post-transcriptionally. A wide variety of tRNA modifications are found in the tRNA anticodon, which are crucial for precise codon recognition and reading frame maintenance, thereby ensuring accurate and efficient protein synthesis. In addition, tRNA-body regions are also frequently modified and thus stabilized in the cell. Over the past two decades, 16 novel tRNA modifications were discovered in various organisms, and the chemical space of tRNA modification continues to expand. Recent studies have revealed that tRNA modifications can be dynamically altered in response to levels of cellular metabolites and environmental stresses. Importantly, we now understand that deficiencies in tRNA modification can have pathological consequences, which are termed 'RNA modopathies'. Dysregulation of tRNA modification is involved in mitochondrial diseases, neurological disorders and cancer.
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43
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Klingl YE, Pakravan D, Van Den Bosch L. Opportunities for histone deacetylase inhibition in amyotrophic lateral sclerosis. Br J Pharmacol 2021; 178:1353-1372. [PMID: 32726472 PMCID: PMC9327724 DOI: 10.1111/bph.15217] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/03/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. ALS patients suffer from a progressive loss of motor neurons, leading to respiratory failure within 3 to 5 years after diagnosis. Available therapies only slow down the disease progression moderately or extend the lifespan by a few months. Epigenetic hallmarks have been linked to the disease, creating an avenue for potential therapeutic approaches. Interference with one class of epigenetic enzymes, histone deacetylases, has been shown to affect neurodegeneration in many preclinical models. Consequently, it is crucial to improve our understanding about histone deacetylases and their inhibitors in (pre)clinical models of ALS. We conclude that selective inhibitors with high tolerability and safety and sufficient blood-brain barrier permeability will be needed to interfere with both epigenetic and non-epigenetic targets of these enzymes. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.
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Affiliation(s)
- Yvonne E. Klingl
- Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI)KU Leuven‐University of LeuvenLeuvenBelgium
- Laboratory of NeurobiologyVIB, Center for Brain & Disease ResearchLeuvenBelgium
| | - Donya Pakravan
- Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI)KU Leuven‐University of LeuvenLeuvenBelgium
- Laboratory of NeurobiologyVIB, Center for Brain & Disease ResearchLeuvenBelgium
| | - Ludo Van Den Bosch
- Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI)KU Leuven‐University of LeuvenLeuvenBelgium
- Laboratory of NeurobiologyVIB, Center for Brain & Disease ResearchLeuvenBelgium
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Jonkhout N, Cruciani S, Santos Vieira HG, Tran J, Liu H, Liu G, Pickford R, Kaczorowski D, Franco GR, Vauti F, Camacho N, Abedini SS, Najmabadi H, Ribas de Pouplana L, Christ D, Schonrock N, Mattick JS, Novoa EM. Subcellular relocalization and nuclear redistribution of the RNA methyltransferases TRMT1 and TRMT1L upon neuronal activation. RNA Biol 2021; 18:1905-1919. [PMID: 33499731 DOI: 10.1080/15476286.2021.1881291] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
RNA modifications are dynamic chemical entities that expand the RNA lexicon and regulate RNA fate. The most abundant modification present in mRNAs, N6-methyladenosine (m6A), has been implicated in neurogenesis and memory formation. However, whether additional RNA modifications may be playing a role in neuronal functions and in response to environmental queues is largely unknown. Here we characterize the biochemical function and cellular dynamics of two human RNA methyltransferases previously associated with neurological dysfunction, TRMT1 and its homolog, TRMT1-like (TRMT1L). Using a combination of next-generation sequencing, LC-MS/MS, patient-derived cell lines and knockout mouse models, we confirm the previously reported dimethylguanosine (m2,2G) activity of TRMT1 in tRNAs, as well as reveal that TRMT1L, whose activity was unknown, is responsible for methylating a subset of cytosolic tRNAAla(AGC) isodecoders at position 26. Using a cellular in vitro model that mimics neuronal activation and long term potentiation, we find that both TRMT1 and TRMT1L change their subcellular localization upon neuronal activation. Specifically, we observe a major subcellular relocalization from mitochondria and other cytoplasmic domains (TRMT1) and nucleoli (TRMT1L) to different small punctate compartments in the nucleus, which are as yet uncharacterized. This phenomenon does not occur upon heat shock, suggesting that the relocalization of TRMT1 and TRMT1L is not a general reaction to stress, but rather a specific response to neuronal activation. Our results suggest that subcellular relocalization of RNA modification enzymes may play a role in neuronal plasticity and transmission of information, presumably by addressing new targets.
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Affiliation(s)
- Nicky Jonkhout
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, Spain
| | - Sonia Cruciani
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, Spain.,University Pompeu Fabra (UPF), Barcelona, Spain
| | - Helaine Graziele Santos Vieira
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, Spain
| | - Julia Tran
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Huanle Liu
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, Spain
| | - Ganqiang Liu
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Current Address: School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Russell Pickford
- Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW, Australia
| | | | - Gloria R Franco
- Departamento De Bioquímica E Imunologia, Universidade Federal De Minas Gerais,Belo Horizonte,Minas Gerais, Brazil
| | - Franz Vauti
- Division of Cellular & Molecular Neurobiology, Zoological Institute, Technische Universität Braunschweig, 38106 Braunschweig, Germany
| | - Noelia Camacho
- Institute for Research in Biomedicine, Barcelona, Catalonia, Spain
| | - Seyedeh Sedigheh Abedini
- Department of Genetics, Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Hossein Najmabadi
- Department of Genetics, Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.,Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran
| | - Lluís Ribas de Pouplana
- Institute for Research in Biomedicine, Barcelona, Catalonia, Spain.,Catalan Institution for Research and Advanced Studies, Barcelona, Catalonia, Spain
| | - Daniel Christ
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Nicole Schonrock
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - John S Mattick
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Eva Maria Novoa
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, Spain.,University Pompeu Fabra (UPF), Barcelona, Spain
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45
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Chujo T, Tomizawa K. Human transfer RNA modopathies: diseases caused by aberrations in transfer RNA modifications. FEBS J 2021; 288:7096-7122. [PMID: 33513290 PMCID: PMC9255597 DOI: 10.1111/febs.15736] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/13/2020] [Accepted: 01/27/2021] [Indexed: 12/14/2022]
Abstract
tRNA molecules are post-transcriptionally modified by tRNA modification enzymes. Although composed of different chemistries, more than 40 types of human tRNA modifications play pivotal roles in protein synthesis by regulating tRNA structure and stability as well as decoding genetic information on mRNA. Many tRNA modifications are conserved among all three kingdoms of life, and aberrations in various human tRNA modification enzymes cause life-threatening diseases. Here, we describe the class of diseases and disorders caused by aberrations in tRNA modifications as 'tRNA modopathies'. Aberrations in over 50 tRNA modification enzymes are associated with tRNA modopathies, which most frequently manifest as dysfunctions of the brain and/or kidney, mitochondrial diseases, and cancer. However, the molecular mechanisms that link aberrant tRNA modifications to human diseases are largely unknown. In this review, we provide a comprehensive compilation of human tRNA modification functions, tRNA modification enzyme genes, and tRNA modopathies, and we summarize the elucidated pathogenic mechanisms underlying several tRNA modopathies. We will also discuss important questions that need to be addressed in order to understand the molecular pathogenesis of tRNA modopathies.
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Affiliation(s)
- Takeshi Chujo
- Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Japan
| | - Kazuhito Tomizawa
- Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Japan
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Smejda M, Kądziołka D, Radczuk N, Krutyhołowa R, Chramiec-Głąbik A, Kędracka-Krok S, Jankowska U, Biela A, Glatt S. Same but different - Molecular comparison of human KTI12 and PSTK. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:118945. [PMID: 33417976 DOI: 10.1016/j.bbamcr.2020.118945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 12/01/2020] [Accepted: 12/23/2020] [Indexed: 11/18/2022]
Abstract
Kti12 and PSTK are closely related and highly similar proteins implicated in different aspects of tRNA metabolism. Kti12 has been identified as an essential regulatory factor of the Elongator complex, involved in the modification of uridine bases in eukaryotic tRNAs. PSTK phosphorylates the tRNASec-bound amino acid serine, which is required to synthesize selenocysteine. Kti12 and PSTK have previously been studied independently in various organisms, but only appear simultaneously in some animalia, including humans. As Kti12- and PSTK-related pathways are clinically relevant, it is of prime importance to understand their biological functions and mutual relationship in humans. Here, we use different tRNA substrates to directly compare the enzymatic activities of purified human KTI12 and human PSTK proteins. Our complementary Co-IP and BioID2 approaches in human cells confirm that Elongator is the main interaction partner of KTI12 but additionally indicate potential links to proteins involved in vesicular transport, RNA metabolism and deubiquitination. Moreover, we identify and validate a yet uncharacterized interaction between PSTK and γ-taxilin. Foremost, we demonstrate that human KTI12 and PSTK do not share interactors or influence their respective biological functions. Our data provide a comprehensive analysis of the regulatory networks controlling the activity of the human Elongator complex and selenocysteine biosynthesis.
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Affiliation(s)
- Marta Smejda
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Dominika Kądziołka
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
| | - Natalia Radczuk
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
| | - Rościsław Krutyhołowa
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | | | - Sylwia Kędracka-Krok
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Urszula Jankowska
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland
| | - Anna Biela
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland.
| | - Sebastian Glatt
- Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland.
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Yamaguchi M, Omori K, Asada S, Yoshida H. Epigenetic Regulation of ALS and CMT: A Lesson from Drosophila Models. Int J Mol Sci 2021; 22:ijms22020491. [PMID: 33419039 PMCID: PMC7825332 DOI: 10.3390/ijms22020491] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/01/2021] [Accepted: 01/03/2021] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disorder and is sometimes associated with frontotemporal dementia. Charcot–Marie–Tooth disease (CMT) is one of the most commonly inherited peripheral neuropathies causing the slow progression of sensory and distal muscle defects. Of note, the severity and progression of CMT symptoms markedly vary. The phenotypic heterogeneity of ALS and CMT suggests the existence of modifiers that determine disease characteristics. Epigenetic regulation of biological functions via gene expression without alterations in the DNA sequence may be an important factor. The methylation of DNA, noncoding RNA, and post-translational modification of histones are the major epigenetic mechanisms. Currently, Drosophila is emerging as a useful ALS and CMT model. In this review, we summarize recent studies linking ALS and CMT to epigenetic regulation with a strong emphasis on approaches using Drosophila models.
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Affiliation(s)
- Masamitsu Yamaguchi
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan; (K.O.); (S.A.)
- Kansai Gakken Laboratory, Kankyo Eisei Yakuhin Co. Ltd., Seika-cho, Kyoto 619-0237, Japan
- Correspondence: (M.Y.); (H.Y.)
| | - Kentaro Omori
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan; (K.O.); (S.A.)
| | - Satoshi Asada
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan; (K.O.); (S.A.)
| | - Hideki Yoshida
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan; (K.O.); (S.A.)
- Correspondence: (M.Y.); (H.Y.)
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48
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Pathogenic Genome Signatures That Damage Motor Neurons in Amyotrophic Lateral Sclerosis. Cells 2020; 9:cells9122687. [PMID: 33333804 PMCID: PMC7765192 DOI: 10.3390/cells9122687] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/04/2020] [Accepted: 12/09/2020] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease and a neurodegenerative disorder, affecting the upper and/or lower motor neurons. Notably, it invariably leads to death within a few years of onset. Although most ALS cases are sporadic, familial amyotrophic lateral sclerosis (fALS) forms 10% of the cases. In 1993, the first causative gene (SOD1) of fALS was identified. With rapid advances in genetics, over fifty potentially causative or disease-modifying genes have been found in ALS so far. Accordingly, routine diagnostic tests should encompass the oldest and most frequently mutated ALS genes as well as several new important genetic variants in ALS. Herein, we discuss current literatures on the four newly identified ALS-associated genes (CYLD, S1R, GLT8D1, and KIF5A) and the previously well-known ALS genes including SOD1, TARDBP, FUS, and C9orf72. Moreover, we review the pathogenic implications and disease mechanisms of these genes. Elucidation of the cellular and molecular functions of the mutated genes will bring substantial insights for the development of therapeutic approaches to treat ALS.
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Toral-Lopez J, Huerta LMG, Messina-Baas O, Cuevas-Covarrubias SA. Submicroscopic 11p13 deletion including the elongator acetyltransferase complex subunit 4 gene in a girl with language failure, intellectual disability and congenital malformations: A case report. World J Clin Cases 2020; 8:5296-5303. [PMID: 33269262 PMCID: PMC7674752 DOI: 10.12998/wjcc.v8.i21.5296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/08/2020] [Accepted: 09/18/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND We described the main features of an infant diagnosed with facial dysmorphic, language failure, intellectual disability and congenital malformations to strengthen our understanding of the disease. Currently, treatment is only rehabilitation and surgery for cleft lip and palate. CASE SUMMARY The proband was a 2-years-8-months-old girl. Familial history was negative for congenital malformations or intellectual disability. The patient had microcephaly, upward-slanting palpebral fissures, depressed nasal bridge, bulbous nose and bilateral cleft lip and palate. Brain magnetic resonance imaging showed cortical atrophy and band heterotopia. Her motor and intellectual development is delayed. A submicroscopic deletion in 11p13 involving the elongator acetyltransferase complex subunit 4 gene (ELP4) and a loss of heterozygosity in Xq25-q26.3 were detected. CONCLUSION There is no treatment for the ELP4 deletion caused by a submicroscopic 11p3 deletion. We describe a second case of deletion of the ELP4 gene without aniridia, which confirms the association between ELP4 gene with several defects and absence of this ocular defect. Additional clinical data in the deletion of the ELP4 gene as cleft palate, facial dysmorphism, and changes at level brain could be associated to this gene or be part of the effect of the recessives genes involved in the loss of heterozygosity region of Xq25-26.3.
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Affiliation(s)
- Jaime Toral-Lopez
- Departamento de Genética Medica, Centro Medico Ecatepec, ISSEMYM, Ecatepec 55000, México
- Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud/Hospital Infantil de México, Universidad Nacional Autónoma de México, México 06720, México
| | | | - Olga Messina-Baas
- Departamento de Oftalmología, Hospital General de México, Cuauhtémoc 06720, México
| | - Sergio A Cuevas-Covarrubias
- Genetica, Hospital General de México, Cuauhtémoc 06726, Mexico
- Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud, Universidad Nacional Autónoma de México, México 06720, Mexico
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50
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Abbassi NEH, Biela A, Glatt S, Lin TY. How Elongator Acetylates tRNA Bases. Int J Mol Sci 2020; 21:E8209. [PMID: 33152999 PMCID: PMC7663514 DOI: 10.3390/ijms21218209] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 12/13/2022] Open
Abstract
Elp3, the catalytic subunit of the eukaryotic Elongator complex, is a lysine acetyltransferase that acetylates the C5 position of wobble-base uridines (U34) in transfer RNAs (tRNAs). This Elongator-dependent RNA acetylation of anticodon bases affects the ribosomal translation elongation rates and directly links acetyl-CoA metabolism to both protein synthesis rates and the proteome integrity. Of note, several human diseases, including various cancers and neurodegenerative disorders, correlate with the dysregulation of Elongator's tRNA modification activity. In this review, we focus on recent findings regarding the structure of Elp3 and the role of acetyl-CoA during its unique modification reaction.
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Affiliation(s)
- Nour-el-Hana Abbassi
- Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland; (N.-e.-H.A.); (A.B.)
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Anna Biela
- Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland; (N.-e.-H.A.); (A.B.)
| | - Sebastian Glatt
- Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland; (N.-e.-H.A.); (A.B.)
| | - Ting-Yu Lin
- Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland; (N.-e.-H.A.); (A.B.)
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