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1
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Key J, Almaguer-Mederos LE, Kandi AR, Sen NE, Gispert S, Köpf G, Meierhofer D, Auburger G. ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation. Neurobiol Dis 2025; 209:106903. [PMID: 40220918 DOI: 10.1016/j.nbd.2025.106903] [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: 02/27/2025] [Revised: 04/04/2025] [Accepted: 04/04/2025] [Indexed: 04/14/2025] Open
Abstract
The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly perinuclear, more abundant, and essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. In this study, we utilized two approaches to clarify the roles of ATXN2L. First, we identified interactors through co-immunoprecipitation in both wild-type and ATXN2L-null murine embryonic fibroblasts. Second, we assessed the proteome profile effects using mass spectrometry in these cells. Additionally, we examined the accumulation of ATXN2L interactors in the SCA2 mouse model, Atxn2-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL, exhibit a stronger association with ATXN2L compared to established interactors like ATXN2, PABPC1, LSM12, and G3BP2. Additionally, ATXN2L interacted with components of the actin complex, such as SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. We noted that oxidative stress increased HNRNPK but decreased SYNE2 association, which likely reflects the relocalization of SG. Proteome profiling revealed that NUFIP2 and SYNE2 are depleted in ATXN2L-null fibroblasts. Furthermore, NUFIP2 homodimers and SYNE1 accumulate during the ATXN2 aggregation process in KIN 14-month-old spinal cord tissues. The functions of ATXN2L and its interactors are therefore critical in RNA granule trafficking and surveillance, particularly for the maintenance of differentiated neurons.
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Affiliation(s)
- Jana Key
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - Luis-Enrique Almaguer-Mederos
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - Arvind Reddy Kandi
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - Nesli-Ece Sen
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - Suzana Gispert
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - Gabriele Köpf
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
| | - David Meierhofer
- Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
| | - Georg Auburger
- Goethe University Frankfurt, University Hospital, Clinic of Neurology, Experimental Neurology, Heinrich- Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany; Institute for Clinical Neuroanatomy, Dr. Senckenberg Anatomy, Fachbereich Medizin, Goethe University Frankfurt, Frankfurt am Main, Germany.
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2
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Wang D, Wang Y, Peng Y, Peng L. Utilizing multi-omics analysis, a new signature has been identified and validated for predicting prognosis and response to immunotherapy in lung squamous cell carcinoma, which is based on tumor mutation burden. Discov Oncol 2025; 16:539. [PMID: 40240626 PMCID: PMC12003222 DOI: 10.1007/s12672-025-02166-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 03/18/2025] [Indexed: 04/18/2025] Open
Abstract
Immunotherapy is used extensively in treating non-small cell lung cancer (NSCLC) patients. Nevertheless, in contrast to lung adenocarcinoma (LUAD), the endeavors to develop effective targeted treatments for lung squamous cell carcinoma (LUSC) have not yielded positive outcomes. Hence, it is crucial to discover biomarkers for immunotherapy and investigate more potent treatments, which is an immediate requirement for individuals with LUSC. The LUSC somatic mutation data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Multivariate analysis was performed to create a signature related to tumor mutation burden (TMB). Next, we utilized the CIBERSORT algorithm to assess the correlation between TMB and immune infiltrates. Additionally, we identified prognostic immune cells of LUSC through Kaplan-Meier analysis. The TCGA and ICGC cohorts covered a combined total of 11 genes that were frequently mutated. SYNE1 and TTN mutation correlated with an increased TMB and suggested a positive clinical outlook. A TMB-related signature (SYNE1 and TTN) was constructed based on this. The outlook for the high-risk group in LUSC was considerably poorer than the low-risk group (p = 0.004). In LUSC, there was a correlation between the TMB-related signature and immune infiltrates, and a positive response to anti-PD-L1 therapy was observed in individuals with low-risk scores. Furthermore, based on Kaplan-Meier analysis, plasma cells were identified as predictive immune cells in LUSC samples. In conclusion, the GSEA examination demonstrated that the TMB-associated signature stimulated immune system-related signaling pathways. To sum up, the TMB-associated signature could be marker to anticipate the immune reaction in individuals with LUSC.
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Affiliation(s)
- Dongguang Wang
- Department of Agriculture and Biotechnology, Hunan University of Humanities, Science and Technology, Loudi, 417000, China
- The Innovation and Entrepreneurship Education Center for Agricultural Biotechnology of Hunan Province, Loudi, 417000, China
| | - Yan Wang
- Department of Agriculture and Biotechnology, Hunan University of Humanities, Science and Technology, Loudi, 417000, China
- The Innovation and Entrepreneurship Education Center for Agricultural Biotechnology of Hunan Province, Loudi, 417000, China
| | - Yiqun Peng
- Department of Agriculture and Biotechnology, Hunan University of Humanities, Science and Technology, Loudi, 417000, China
- The Innovation and Entrepreneurship Education Center for Agricultural Biotechnology of Hunan Province, Loudi, 417000, China
| | - Liang Peng
- Department of Nephrology, The Second Affiliated Hospital of University of South China, Hengyang, 421001, China.
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Pekeles H, Myers KA. Intrafamilial Phenotypic Variability in SYNE1-Related Disorder. Am J Med Genet A 2025; 197:e63858. [PMID: 39215516 DOI: 10.1002/ajmg.a.63858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/10/2024] [Accepted: 08/18/2024] [Indexed: 09/04/2024]
Affiliation(s)
- Heather Pekeles
- Division of Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Canada
| | - Kenneth A Myers
- Division of Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Medical Centre, Montreal, Canada
- Department of Neurology and Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Canada
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4
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Jaques CS, Gama MTD, de Oliveira RA, Rezende TJ, Tonholo Silva TY, França MC, Bezerra MLE, Barsottini OG, Pedroso JL. Natural History of Dystonia in SYNE1 Ataxia: A Clinical, Imaging and Neurophysiological Observation. Mov Disord Clin Pract 2025; 12:100-104. [PMID: 39382210 PMCID: PMC11736882 DOI: 10.1002/mdc3.14224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/16/2024] [Indexed: 10/10/2024] Open
Affiliation(s)
- Cristina Saade Jaques
- Department of Neurology, Ataxia UnitUniversidade Federal de São PauloSão PauloBrazil
| | | | | | | | | | | | | | | | - José Luiz Pedroso
- Department of Neurology, Ataxia UnitUniversidade Federal de São PauloSão PauloBrazil
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5
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Morton GM, Toledo MP, Zheng C, Zheng Y, Megraw TL. A distinct isoform of Msp300 (nesprin) organizes the perinuclear microtubule organizing center in adipocytes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.28.601268. [PMID: 38979285 PMCID: PMC11230431 DOI: 10.1101/2024.06.28.601268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
In many cell types, disparate non-centrosomal microtubule-organizing centers (ncMTOCs) replace functional centrosomes and serve the unique needs of the cell types in which they are formed. In Drosophila fat body cells (adipocytes), an ncMTOC is organized on the nuclear surface. This perinuclear ncMTOC is anchored by Msp300, encoded by one of two nesprin-encoding genes in Drosophila. Msp300 and the spectraplakin short stop (shot) are co-dependent for localization to the nuclear envelope to generate the ncMTOC where they recruit the microtubule minus-end stabilizer Patronin (CAMSAP). The Msp300 gene is complex, encoding at least eleven isoforms. Here we show that two Msp300 isoforms, Msp300-PE and - PG, are required and only one, Msp300-PE, appears sufficient for generation of the ncMTOC. Loss of Msp300-PE and -PG results in severe loss of localization of shot and Patronin, disruption of the MT array, nuclear mispositioning and loss of endosomal trafficking. Furthermore, upon loss of Msp300-PE and -PG, other isoforms are retained at the nuclear surface despite the loss of nuclear positioning and MT organization, indicating that they are not sufficient to generate the ncMTOC. Msp300-PE has an unusual domain structure including a lack of a KASH domain and very few spectrin repeats and appears therefore to have a highly derived function to generate an ncMTOC on the nuclear surface.
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Affiliation(s)
- Garret M Morton
- Department of Biomedical Sciences, Florida State University, Tallahassee, FL, USA
| | - Maria Pilar Toledo
- Department of Biomedical Sciences, Florida State University, Tallahassee, FL, USA
| | - Chunfeng Zheng
- Department of Biomedical Sciences, Florida State University, Tallahassee, FL, USA
| | - Yiming Zheng
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, China, 361102, and Shenzhen Research Institute of Xiamen University, Shenzhen, China, 518057
| | - Timothy L Megraw
- Department of Biomedical Sciences, Florida State University, Tallahassee, FL, USA
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6
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Kuwako KI, Suzuki S. Diverse Roles of the LINC Complex in Cellular Function and Disease in the Nervous System. Int J Mol Sci 2024; 25:11525. [PMID: 39519078 PMCID: PMC11545860 DOI: 10.3390/ijms252111525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/20/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
The linker of nucleoskeleton and cytoskeleton (LINC) complex, which spans the nuclear envelope, physically connects nuclear components to the cytoskeleton and plays a pivotal role in various cellular processes, including nuclear positioning, cell migration, and chromosomal configuration. Studies have revealed that the LINC complex is essential for different aspects of the nervous system, particularly during development. The significance of the LINC complex in neural lineage cells is further corroborated by the fact that mutations in genes associated with the LINC complex have been implicated in several neurological diseases, including neurodegenerative and psychiatric disorders. In this review, we aimed to summarize the expanding knowledge of LINC complex-related neuronal functions and associated neurological diseases.
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Affiliation(s)
- Ken-ichiro Kuwako
- Department of Neural and Muscular Physiology, School of Medicine, Shimane University, 89-1 Enya-cho, Izumo-shi 693-8501, Shimane, Japan
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7
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Kuchina A, Murtazina A, Borovikov A, Subbotin D, Bardakov S, Akhkiamova M, Nikolaeva A, Shchagina O, Kutsev S. Challenging Diagnosis of a Patient with Two Novel Variants in the SYNE1 Gene. Int J Mol Sci 2024; 25:10841. [PMID: 39409170 PMCID: PMC11476505 DOI: 10.3390/ijms251910841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/02/2024] [Accepted: 10/05/2024] [Indexed: 10/20/2024] Open
Abstract
We report a case of SYNE1-associated autosomal recessive spinocerebellar ataxia (SCAR8) presenting with a complex multisystemic phenotype, including highly elevated creatine kinase levels and lower-leg muscle atrophy. In addition to identifying two novel pathogenic variants in the SYNE1 gene, whole-exome sequencing revealed three variants of uncertain significance in the DYSF gene. Electromyography and muscle magnetic resonance imaging indicated a neurogenic pattern of muscle involvement. These findings, along with the segregation analysis of the variants, allowed us to exclude DYSF-associated muscular dystrophy; however, we cannot entirely rule out the possibility that the DYSF gene variants may act as modifiers of the patient's phenotype.
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Affiliation(s)
- Anna Kuchina
- Research Centre for Medical Genetics, 115478 Moscow, Russia; (A.M.); (A.B.); (D.S.); (M.A.); (A.N.); (O.S.); (S.K.)
| | - Aysylu Murtazina
- Research Centre for Medical Genetics, 115478 Moscow, Russia; (A.M.); (A.B.); (D.S.); (M.A.); (A.N.); (O.S.); (S.K.)
| | - Artem Borovikov
- Research Centre for Medical Genetics, 115478 Moscow, Russia; (A.M.); (A.B.); (D.S.); (M.A.); (A.N.); (O.S.); (S.K.)
| | - Dmitrii Subbotin
- Research Centre for Medical Genetics, 115478 Moscow, Russia; (A.M.); (A.B.); (D.S.); (M.A.); (A.N.); (O.S.); (S.K.)
| | - Sergey Bardakov
- Department of Neurology, S.M. Kirov Military Medical Academy, 194044 St. Petersburg, Russia;
| | - Maria Akhkiamova
- Research Centre for Medical Genetics, 115478 Moscow, Russia; (A.M.); (A.B.); (D.S.); (M.A.); (A.N.); (O.S.); (S.K.)
| | - Aleksandra Nikolaeva
- Research Centre for Medical Genetics, 115478 Moscow, Russia; (A.M.); (A.B.); (D.S.); (M.A.); (A.N.); (O.S.); (S.K.)
| | - Olga Shchagina
- Research Centre for Medical Genetics, 115478 Moscow, Russia; (A.M.); (A.B.); (D.S.); (M.A.); (A.N.); (O.S.); (S.K.)
| | - Sergey Kutsev
- Research Centre for Medical Genetics, 115478 Moscow, Russia; (A.M.); (A.B.); (D.S.); (M.A.); (A.N.); (O.S.); (S.K.)
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8
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Gagnon M, Bouhamdani N, Kolev DP, Askree SH, Ben Amor M. Identification of an intronic Alu insertion in the SYNE1 gene associated with autosomal recessive spinocerebellar ataxia type 8. GENETICS IN MEDICINE OPEN 2024; 2:101893. [PMID: 39669622 PMCID: PMC11613682 DOI: 10.1016/j.gimo.2024.101893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 09/04/2024] [Accepted: 09/05/2024] [Indexed: 12/14/2024]
Affiliation(s)
- Maryse Gagnon
- Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de formation médicale du Nouveau-Brunswick, Moncton, NB, Canada
| | - Nadia Bouhamdani
- Université de Sherbrooke, Sherbrooke, QC, Canada
- Vitalité Health Network, Moncton, NB, Canada
- Université de Moncton, Department of Chemistry and Biochemistry, Moncton, NB, Canada
- Atlantic Cancer Research Institute, Moncton, NB, Canada
| | - Dimiter P. Kolev
- MNG Laboratories (Medical Neurogenetics, LLC.), a Labcorp subsidiary, Atlanta, GA
| | - S. Hussain Askree
- MNG Laboratories (Medical Neurogenetics, LLC.), a Labcorp subsidiary, Atlanta, GA
| | - Mouna Ben Amor
- Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de formation médicale du Nouveau-Brunswick, Moncton, NB, Canada
- Vitalité Health Network, Moncton, NB, Canada
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9
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Mokhtari D, Jahanpanah M, Jabbari N, Azari H, Davarnia S, Mokaber H, Arish S, Molatefi R, Abbasi V, Davarnia B. Genetic investigation of patients with autosomal recessive ataxia and identification of two novel variants in the SQSTM1 and SYNE1 genes. Hum Genome Var 2024; 11:35. [PMID: 39214971 PMCID: PMC11364807 DOI: 10.1038/s41439-024-00292-x] [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: 05/18/2024] [Revised: 07/08/2024] [Accepted: 07/21/2024] [Indexed: 09/04/2024] Open
Abstract
Hereditary ataxias are classified by inheritance patterns into autosomal dominant, autosomal recessive, X-linked, and mitochondrial modes of inheritance. A large group of adult hereditary ataxias have autosomal dominant inheritance, and autosomal recessive cerebellar ataxias (ARCAs) are rare, with greater diversity in phenotypic and genotypic features. Therefore, comprehensive genetic testing is useful for identifying the genes responsible for ARCAs. We identified two novel pathogenic variants of the SQSTM1 and SYNE1 genes via whole-exome sequencing in patients with ARCAs.
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Affiliation(s)
- Diana Mokhtari
- Department of Genetics and Pathology, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mohammad Jahanpanah
- Department of Genetics and Pathology, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Nasim Jabbari
- Department of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Hamed Azari
- Department of Genetics and Pathology, Ardabil University of Medical Sciences, Ardabil, Iran
| | | | - Haleh Mokaber
- Department of Biology, Ardabil Branch, Islamic Azad University, Ardabil, Iran
| | - Sara Arish
- Department of Genetics and Pathology, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Rasol Molatefi
- Department of Pediatrics, Bo-Ali Children's Hospital of Ardabil University of Medical Sciences, Ardabil, Iran
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Vahid Abbasi
- Department of Neurology, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Behzad Davarnia
- Department of Genetics and Pathology, Ardabil University of Medical Sciences, Ardabil, Iran.
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10
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Hammarström K, Nunes L, Mathot L, Mezheyeuski A, Lundin E, Korsavidou Hult N, Imam I, Osterlund E, Sjöblom T, Glimelius B. Clinical and genetic factors associated with tumor response to neoadjuvant (chemo)radiotherapy, survival and recurrence risk in rectal cancer. Int J Cancer 2024; 155:40-53. [PMID: 38376070 DOI: 10.1002/ijc.34880] [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: 08/21/2023] [Revised: 01/14/2024] [Accepted: 01/16/2024] [Indexed: 02/21/2024]
Abstract
Rectal cancer poses challenges in preoperative treatment response, with up to 30% achieving a complete response (CR). Personalized treatment relies on accurate identification of responders at diagnosis. This study aimed to unravel CR determinants, overall survival (OS), and time to recurrence (TTR) using clinical and targeted sequencing data. Analyzing 402 patients undergoing preoperative treatment, tumor stage, size, and treatment emerged as robust response predictors. CR rates were higher in smaller, early-stage, and intensively treated tumors. Targeted sequencing analyzed 216 cases, while 120 patients provided hotspot mutation data. KRAS mutation dramatically reduced CR odds by over 50% (odds ratio [OR] = 0.3 in the targeted sequencing and OR = 0.4 hotspot cohorts, respectively). In contrast, SMAD4 and SYNE1 mutations were associated with higher CR rates (OR = 6.0 and 6.8, respectively). Favorable OS was linked to younger age, CR, and low baseline carcinoembryonic antigen levels. Notably, CR and an APC mutation increased TTR, while a BRAF mutation negatively affected TTR. Beyond tumor burden, SMAD4 and SYNE1 mutations significantly influenced CR. KRAS mutations independently correlated with radiotherapy resistance, and BRAF mutations heightened recurrence risk. Intriguingly, non-responding tumors with initially small sizes carried a higher risk of recurrence. The findings, even if limited in addition to the imperfect clinical factors, offer insights into rectal cancer treatment response, guiding personalized therapeutic strategies. By uncovering factors impacting CR, OS, and TTR, this study underscores the importance of tailored approaches for rectal cancer patients. These findings, based on extensive analysis and mutation data, pave the way for personalized interventions, optimizing outcomes in the challenges of rectal cancer preoperative treatment.
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Affiliation(s)
- Klara Hammarström
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Luís Nunes
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Lucy Mathot
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Artur Mezheyeuski
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Emma Lundin
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | | | - Israa Imam
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Emerik Osterlund
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Tobias Sjöblom
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Bengt Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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11
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Woolley PR, Wen X, Conway OM, Ender NA, Lee JH, Paull TT. Regulation of transcription patterns, poly(ADP-ribose), and RNA-DNA hybrids by the ATM protein kinase. Cell Rep 2024; 43:113896. [PMID: 38442018 PMCID: PMC11022685 DOI: 10.1016/j.celrep.2024.113896] [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: 06/01/2023] [Revised: 01/11/2024] [Accepted: 02/15/2024] [Indexed: 03/07/2024] Open
Abstract
The ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in ataxia-telangiectasia (A-T) patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with the expression level and guanine-cytosine (GC) content of transcribed genes. In human neuron-like cells in culture, we map locations of poly(ADP-ribose) and RNA-DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content. Antioxidant treatment reverses the accumulation of R-loops in transcribed regions, consistent with the central role of reactive oxygen species in promoting these lesions. Based on these results, we postulate that transcription-associated lesions accumulate in ATM-deficient cells and that the single-strand breaks and PARylation at these sites ultimately generate changes in transcription that compromise cerebellum function and lead to neurodegeneration over time in A-T patients.
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Affiliation(s)
- Phillip R Woolley
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
| | - Xuemei Wen
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
| | - Olivia M Conway
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
| | - Nicolette A Ender
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
| | - Ji-Hoon Lee
- Department of Biological Sciences, Research Center of Ecomimetics, Chonnam National University, Gwangju 61186, Republic of Korea.
| | - Tanya T Paull
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
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12
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HARA Y, SHODA A, YONOICHI S, ISHIDA Y, MURATA M, KIMURA M, ITO M, NUNOBIKI S, YOSHIMOTO A, MANTANI Y, YOKOYAMA T, HIRANO T, IKENAKA Y, TABUCHI Y, HOSHI N. No-observed-adverse-effect-level (NOAEL) clothianidin, a neonicotinoid pesticide, impairs hippocampal memory and motor learning associated with alteration of gene expression in cerebellum. J Vet Med Sci 2024; 86:340-348. [PMID: 38311399 PMCID: PMC10963099 DOI: 10.1292/jvms.23-0516] [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: 12/22/2023] [Accepted: 01/24/2024] [Indexed: 02/10/2024] Open
Abstract
Neonicotinoid pesticides (NNs) have been associated with numerous neurobehavioral effects in rodents, raising concerns about their impact on cognitive function. Clothianidin (CLO), a type of NN, was orally administered to male mice (10 weeks old, C57BL/6N) at the no-observed-adverse-effect level (NOAEL) of 50 mg/kg/day as indicated in the pesticide risk assessment report. Behavioral tests (novel location recognition and rotarod tests) evaluated hippocampal memory and cerebellar motor learning. After each test, plasma monoamines (3-methoxytyramine, histamine, serotonin, tryptamine) were measured by LC-ESI/MS/MS (Liquid chromatography-electrospray ionization/tandem mass spectrometry), and cerebellar mRNA expression was quantified by microarray and qRT-PCR analyses. The NOAEL of CLO was found to impair hippocampal memory, leading to decreased spontaneous locomotor activity and motor function. We reported, for the first time, multiple alterations of gene expression in the cerebellum associated with motor dysfunction.
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Affiliation(s)
- Yukako HARA
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Asuka SHODA
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Sakura YONOICHI
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Yuya ISHIDA
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Midori MURATA
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Mako KIMURA
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Makiko ITO
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Sarika NUNOBIKI
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Ayano YOSHIMOTO
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Youhei MANTANI
- Laboratory of Histophysiology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Toshifumi YOKOYAMA
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
| | - Tetsushi HIRANO
- Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Yoshinori IKENAKA
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Hokkaido, Japan
- Translational Research Unit, Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Hokkaido, Japan
- One Health Research Center, Hokkaido University, Hokkaido, Japan
- Water Research Group, Unit for Environmental Sciences and Management, North-West University, Potchefstroom, South Africa
| | - Yoshiaki TABUCHI
- Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Nobuhiko HOSHI
- Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Hyogo, Japan
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Benarroch E. What Is the Role of Nuclear Envelope Proteins in Neurologic Disorders? Neurology 2024; 102:e209202. [PMID: 38330281 DOI: 10.1212/wnl.0000000000209202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 02/10/2024] Open
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Fukushima T, Kobatake K, Miura K, Takemoto K, Yamanaka R, Tasaka R, Kohada Y, Miyamoto S, Sekino Y, Kitano H, Goto K, Ikeda K, Goriki A, Hieda K, Kaminuma O, Hinata N. Nesprin1 Deficiency Is Associated with Poor Prognosis of Renal Cell Carcinoma and Resistance to Sunitinib Treatment. Oncology 2024; 102:868-879. [PMID: 38442705 DOI: 10.1159/000536539] [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: 12/12/2023] [Accepted: 01/20/2024] [Indexed: 03/07/2024]
Abstract
INTRODUCTION Nuclear envelope spectrin repeat protein (Nesprin) 1 encoded by SYNE1, crucially regulates the morphology and functions of the cell. Mutations in the SYNE1 gene are associated with various diseases; however, their significance in renal cell carcinoma (RCC) remains unknown. In this study, we have investigated the association of SYNE1/Nesprin1 with the progression and prognosis of clear cell RCC (ccRCC). METHODS In silico analyses of publicly available datasets of patients with RCC were performed. Based on the cohort data, Nesprin1 expression in nephrectomized tissue samples acquired from patients with ccRCC was analyzed using immunohistochemical staining. The invasion, migration, and proliferation of the SYNE1-knockdown human RCC cell lines were analyzed in vitro; moreover, RNA sequencing and gene set enrichment analysis were conducted to study the molecular mechanism underlying the association of SYNE1/Nesprin1 with prognosis of RCC. RESULTS Patients with RCC-associated SYNE1 gene mutations exhibited significantly worse overall and progression-free survivals. Patients with Nesprin1-negative ccRCC tumors exhibit significantly poorer overall, cancer-specific, and recurrence-free survival rates than those recorded in the Nesprin1-positive group. SYNE1 knockdown enhanced the invasion and migration of RCC cells; however, it did not influence the proliferation of cells. RNA sequencing and gene set enrichment analysis revealed that SYNE1 knockdown significantly altered the expression of genes associated with oxidative phosphorylation. Consistently, patients with RCC exhibiting low SYNE1 expression, who were treated with the vascular endothelial growth factor receptor inhibitor sunitinib, had worse progression-free survival. CONCLUSIONS The results indicate that the expression of SYNE1/Nesprin1 and SYNE1 mutations in patients with RCC are closely linked to their prognosis and responsiveness to sunitinib treatment.
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Affiliation(s)
- Takafumi Fukushima
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan,
| | - Kohei Kobatake
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kento Miura
- Department of Disease Models, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Kenshiro Takemoto
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryoken Yamanaka
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Department of Disease Models, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Ryo Tasaka
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Kohada
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shunsuke Miyamoto
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yohei Sekino
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroyuki Kitano
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keisuke Goto
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenichiro Ikeda
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akihiro Goriki
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keisuke Hieda
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Osamu Kaminuma
- Department of Disease Models, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Nobuyuki Hinata
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Jin S, Xiong Y, Zhang W, Qiao H, Wu Y, Jiang S, Fu H. Identification of Candidate Male-Reproduction-Related Genes from the Testis and Androgenic Gland of Macrobrachium nipponense, Regulated by PDHE1, through Transcriptome Profiling Analysis. Int J Mol Sci 2024; 25:1940. [PMID: 38339218 PMCID: PMC10856083 DOI: 10.3390/ijms25031940] [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: 01/05/2024] [Revised: 01/27/2024] [Accepted: 01/31/2024] [Indexed: 02/12/2024] Open
Abstract
The previous publication identified that pyruvate dehydrogenase E1 (PDHE1) positively regulated the process of male reproduction in M. nipponense through affecting the expressions of insulin-like androgenic gland hormone. The present study aimed to identify the potential male-reproduction-related genes that were regulated by PDHE1 through performing the transcriptome profiling analysis in the testis and androgenic gland after the knockdown of the expressions of PDHE1 by the injection of dsPDHE1. Both RNA-Seq and qPCR analysis identified the significant decreases in PDHE1 expressions in the testis and androgenic gland in dsPDHE1-injected prawns compared to those in dsGFP-injected prawns, indicating the efficiency of dsPDHE1 in the present study. Transcriptome profiling analysis identified 56 and 127 differentially expressed genes (DEGs) in the testis and androgenic gland, respectively. KEGG analysis revealed that the energy-metabolism-related pathways represented the main enriched metabolic pathways of DEGs in both the testis and androgenic gland, including pyruvate metabolism, the Citrate cycle (TCA cycle), Glycolysis/Gluconeogenesis, and the Glucagon signaling pathway. Thus, it is predicted that these metabolic pathways and the DEGs from these metabolic pathways regulated by PDHE1 may be involved in the regulation of male reproduction in M. nipponense. Furthermore, four genes were found to be differentially expressed in both the testis and androgenic gland, of which ribosomal protein S3 was down-regulated and uncharacterized protein LOC113829596 was up-regulated in both the testis and androgenic gland in dsPDHE1-injected prawns. The present study provided valuable evidence for the establishment of an artificial technique to regulate the process of male reproduction in M. nipponense.
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Affiliation(s)
- Shubo Jin
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; (Y.X.); (W.Z.); (H.Q.); (Y.W.); (S.J.)
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China
| | - Yiwei Xiong
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; (Y.X.); (W.Z.); (H.Q.); (Y.W.); (S.J.)
| | - Wenyi Zhang
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; (Y.X.); (W.Z.); (H.Q.); (Y.W.); (S.J.)
| | - Hui Qiao
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; (Y.X.); (W.Z.); (H.Q.); (Y.W.); (S.J.)
| | - Yan Wu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; (Y.X.); (W.Z.); (H.Q.); (Y.W.); (S.J.)
| | - Sufei Jiang
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; (Y.X.); (W.Z.); (H.Q.); (Y.W.); (S.J.)
| | - Hongtuo Fu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; (Y.X.); (W.Z.); (H.Q.); (Y.W.); (S.J.)
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China
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Nuzhnyi EP, Protopopova AO, Abramycheva NY, Protsenko AR, Illarioshkin SN. [Rare forms of autosomal recessive spinocerebellar ataxia associated with mutations in the ANO10 (ATX-ANO10) and SYNE1 (ATX-SYNE1) genes]. Zh Nevrol Psikhiatr Im S S Korsakova 2024; 124:32-38. [PMID: 39269294 DOI: 10.17116/jnevro202412408132] [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] [Indexed: 09/15/2024]
Abstract
OBJECTIVE To analyze clinical and genetic characteristics of patients with the verified rare forms of autosomal recessive spinocerebellar ataxias, ATX-ANO10 and ATX-SYNE1. MATERIAL AND METHODS Six unrelated patients with established diagnoses were examined: 4 patients with ATX-ANO10 and 2 patients with ATX-SYNE1. Brain MRI and nerve conduction study were performed. To screen for cognitive impairment, the scale for the Assessment and Rating of Ataxia (SARA), and the Montreal Cognitive Assessment Scale (MoCA) were used. Mutation screening included panel sequencing on the Illumina MiSeq platform. RESULTS Six variants were found in the ANO10 gene: the previously described pathogenic nonsense mutations c.G1025A (p.W342X) and c.C1244G (p.S415X), as well as novel probably pathogenic variants c.1477-2A>G and c.G101T (p.W34L) and missense mutations c.A110C (p.N37T) and c.T104C (p.L35P) of undetermined significance. A novel nonsense mutation c.C8911T (p.Q2971X) and a previously described pathogenic variant c.C4939T (p.Q1647X) were found in the SYNE1 gene. The clinical presentation of the ATX-ANO10 and ATX-SYNE1 was typical presenting with slowly progressive cerebellar ataxia with pyramidal signs, with young onset and cerebellar atrophy according to brain MRI study. CONCLUSION We provided first-ever data on clinical features and mutation spectrum In Russian patients with ATX-ANO10 and ATX-SYNE1. The phenotype of these ataxias is nonspecific, so the method of choice for molecular diagnostics is massive parallel sequencing.
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Affiliation(s)
- E P Nuzhnyi
- Research Center of Neurology, Moscow, Russia
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Baskar D, Preethish-Kumar V, Polavarapu K, Vengalil S, Nashi S, Menon D, Ganaraja VH, Girija MS, Nandeesh BN, Arunachal G, Nalini A. Clinical and Genetic Heterogeneity of Nuclear Envelopathy Related Muscular Dystrophies in an Indian Cohort. J Neuromuscul Dis 2024; 11:969-979. [PMID: 39058449 PMCID: PMC11380268 DOI: 10.3233/jnd-230172] [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] [Indexed: 07/28/2024]
Abstract
Introduction Nuclear envelopathies occur due to structural and/or functional defects in various nuclear envelope proteins such as lamin A/C and lamin related proteins. This study is the first report on the phenotype-genotype patterns of nuclear envelopathy-related muscular dystrophies from India. Methods In this retrospective study, we have described patients with genetically confirmed muscular dystrophy associated with nuclear envelopathy. Data on clinical, laboratory findings and muscle MRI were collected. Results Sixteen patients were included with median age at onset of 3 years (range: 1 month - 17 years). Three genes were involved: LMNA (11, 68.75%), EMD (4, 25%) and SYNE1 (1, 6.25%). The 11 patients with LMNA variants were Congenital muscular dystrophy (MDCL)=4, Limb Girdle Muscular Dystrophy (LGMD1B)=4 and Emery-Dreifuss Muscular Dystrophy (EDMD2)=3. On muscle biopsy, one patient from each laminopathy phenotype (n = 3) revealed focal perivascular inflammatory infiltrate. Other notable features were ophthalmoparesis in one and facial weakness in one. None had cardiac involvement. Patients with EDMD1 had both upper (UL) and lower limb (LL) proximo-distal weakness. Cardiac rhythm disturbances such as sick sinus syndrome and atrial arrhythmias were noted in two patients with EDMD1. Only one patient with variant c.654_658dup (EMD) lost ambulation in the 3rd decade, 18 years after disease onset. Two had finger contractures with EMD and SYNE1 variants respectively. All patients with LMNA and SYNE1 variants were ambulant at the time of evaluation. Mean duration of illness (years) was 11.6±13 (MDCL), 3.2±1.0 (EDMD2), 10.4±12.8 (LGMD1B), 11.8±8.4 (EDMD1) and 3 (EDMD4). One patient had a novel SYNE1 mutation (c.22472dupA, exon 123) and presented with UL phenotype and prominent finger and wrist contractures. Conclusion The salient features included ophthalmoparesis and facial weakness in LMNA, prominent finger contractures in EMD and SYNE1 and upper limb phenotype with the novel pathogenic variant in SYNE1.
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Affiliation(s)
- Dipti Baskar
- Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | | | - Kiran Polavarapu
- Department of Medicine, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa and Division of Neurology, The Ottawa Hospital, Ottawa, Canada
| | - Seena Vengalil
- Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Saraswati Nashi
- Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Deepak Menon
- Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | | | - Manu Santhappan Girija
- Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | | | - Gautham Arunachal
- Department of Human Genetics, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Atchayaram Nalini
- Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
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Konstantinidis G, Tavernarakis N. In Vivo Monitoring of Nucleophagy in Caenorhabditis elegans. Methods Mol Biol 2024; 2845:67-77. [PMID: 39115658 DOI: 10.1007/978-1-0716-4067-8_6] [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] [Indexed: 01/04/2025]
Abstract
The autophagy-lysosomal pathway enables the controlled degradation of cellular contents. Nucleophagy is the selective autophagic recycling of nuclear components upon delivery to the lysosome. Although methods to monitor and quantify autophagy as well as selective types of autophagy have been developed and implemented in cells and in vivo, methods monitoring nucleophagy remain scarce. Here, we describe a procedure to monitor the autophagic engagement of an endogenous nuclear envelope component, i.e., ANC-1, the nematode homologue of the mammalian Nesprins in vivo, utilizing super-resolution microscopy.
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Affiliation(s)
- Georgios Konstantinidis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece.
- Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece.
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Woolley PR, Wen X, Conway OM, Ender NA, Lee JH, Paull TT. Regulation of transcription patterns, poly-ADP-ribose, and RNA-DNA hybrids by the ATM protein kinase. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.06.570417. [PMID: 38106035 PMCID: PMC10723464 DOI: 10.1101/2023.12.06.570417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
The ATM protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in Ataxia-telangiectasia patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with expression level and GC content of transcribed genes. In human neuron-like cells in culture we map locations of poly-ADP-ribose and RNA-DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content. Antioxidant treatment reverses the accumulation of R-loops in transcribed regions, consistent with the central role of ROS in promoting these lesions. Based on these results we postulate that transcription-associated lesions accumulate in ATM-deficient cells and that the single-strand breaks and PARylation at these sites ultimately generate changes in transcription that compromise cerebellum function and lead to neurodegeneration over time in A-T patients.
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Affiliation(s)
- Phillip R. Woolley
- The University of Texas at Austin, Department of Molecular Biosciences, Austin, TX, 78712
| | - Xuemei Wen
- The University of Texas at Austin, Department of Molecular Biosciences, Austin, TX, 78712
| | - Olivia M. Conway
- The University of Texas at Austin, Department of Molecular Biosciences, Austin, TX, 78712
| | - Nicolette A. Ender
- The University of Texas at Austin, Department of Molecular Biosciences, Austin, TX, 78712
| | - Ji-Hoon Lee
- Department of Biological Sciences, Research Center of Ecomimetics, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Tanya T. Paull
- The University of Texas at Austin, Department of Molecular Biosciences, Austin, TX, 78712
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Yerima G, Domkam N, Ornowski J, Jahed Z, Mofrad MRK. Force transmission and SUN-KASH higher-order assembly in the LINC complex models. Biophys J 2023; 122:4582-4597. [PMID: 37924205 PMCID: PMC10719071 DOI: 10.1016/j.bpj.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 09/14/2023] [Accepted: 11/01/2023] [Indexed: 11/06/2023] Open
Abstract
The linkers of the nucleoskeleton and cytoskeleton (LINC) complex comprises Sad-1 and UNC-84 (SUN) and Klarsicht, ANC-1, SYNE homology (KASH) domain proteins, whose conserved interactions provide a physical coupling between the cytoskeleton and the nucleoskeleton, thereby mediating the transfer of physical forces across the nuclear envelope. The LINC complex can perform distinct cellular functions by pairing various KASH domain proteins with the same SUN domain protein. Recent studies have suggested a higher-order assembly of SUN and KASH instead of a more widely accepted linear trimer model for the LINC complex. In the present study, we use molecular dynamics simulations to investigate the mechanism of force transfer across the two proposed models of LINC complex assembly, namely the 3:3 linear trimer model and the 6:6 higher-order model. Employing steered molecular dynamics simulations with various structures using forces at different rates and directions, we examine the structural stability of the two models under various biologically relevant conditions. Our results suggest that both models can withstand and transfer significant levels of force while retaining their structural integrity. However, the force response of various SUN/KASH assemblies depend on the force direction and pulling rates. Slower pulling rates result in higher mean square fluctuations of the 3:3 assembly compared to the fast pulling. Interestingly, the 6:6 assembly tends to provide an additional range of motion flexibility and might be more advantageous to the structural rigidity and pliability of the nuclear envelope. These findings offer insights into how the SUN and KASH proteins maintain the structural integrity of the nuclear membrane.
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Affiliation(s)
- Ghafar Yerima
- Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, California
| | - Nya Domkam
- Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, California
| | - Jessica Ornowski
- Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, California
| | - Zeinab Jahed
- Department of Nanoengineering, Jacobs School of Engineering, University of California, San Diego, California.
| | - Mohammad R K Mofrad
- Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, California; Molecular Biophysics and Integrative Bioimaging Division, Lawrence Berkeley National Lab, Berkeley, California.
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Serag M, Plutino M, Charles P, Azulay JP, Chaussenot A, Paquis-Flucklinger V, Ait-El-Mkadem Saadi S, Rouzier C. A Case Report of SYNE1 Deficiency-Mimicking Mitochondrial Disease and the Value of Pangenomic Investigations. Genes (Basel) 2023; 14:2154. [PMID: 38136976 PMCID: PMC10743207 DOI: 10.3390/genes14122154] [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: 11/08/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
Mitochondrial disorders are characterized by a huge clinical, biochemical, and genetic heterogeneity, which poses significant diagnostic challenges. Several studies report that more than 50% of patients with suspected mitochondrial disease could have a non-mitochondrial disorder. Thus, only the identification of the causative pathogenic variant can confirm the diagnosis. Herein, we describe the diagnostic journey of a family suspected of having a mitochondrial disorder who were referred to our Genetics Department. The proband presented with the association of cerebellar ataxia, COX-negative fibers on muscle histology, and mtDNA deletions. Whole exome sequencing (WES), supplemented by a high-resolution array, comparative genomic hybridization (array-CGH), allowed us to identify two pathogenic variants in the non-mitochondrial SYNE1 gene. The proband and her affected sister were found to be compound heterozygous for a known nonsense variant (c.13258C>T, p.(Arg4420Ter)), and a large intragenic deletion that was predicted to result in a loss of function. To our knowledge, this is the first report of a large intragenic deletion of SYNE1 in patients with cerebellar ataxia (ARCA1). This report highlights the interest in a pangenomic approach to identify the genetic basis in heterogeneous neuromuscular patients with the possible cause of mitochondrial disease. Moreover, even rare copy number variations should be considered in patients with a phenotype suggestive of SYNE1 deficiency.
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Affiliation(s)
- Mounir Serag
- Service de Génétique Médicale, Hôpital l’Archet 2, CHU de Nice, 151 Route Saint-Antoine de Ginestière, 06202 Nice, France; (M.S.); (M.P.); (A.C.); (V.P.-F.); (S.A.-E.-M.S.)
- CNRS UMR7284/ INSERM U1081, Faculté de Médecine, Université Côte d’Azur, 06107 Nice, France
| | - Morgane Plutino
- Service de Génétique Médicale, Hôpital l’Archet 2, CHU de Nice, 151 Route Saint-Antoine de Ginestière, 06202 Nice, France; (M.S.); (M.P.); (A.C.); (V.P.-F.); (S.A.-E.-M.S.)
- CNRS UMR7284/ INSERM U1081, Faculté de Médecine, Université Côte d’Azur, 06107 Nice, France
| | - Perrine Charles
- Service de Génétique, La Pitié-Salpêtrière, AP-HP, 75610 Paris, France;
| | | | - Annabelle Chaussenot
- Service de Génétique Médicale, Hôpital l’Archet 2, CHU de Nice, 151 Route Saint-Antoine de Ginestière, 06202 Nice, France; (M.S.); (M.P.); (A.C.); (V.P.-F.); (S.A.-E.-M.S.)
- CNRS UMR7284/ INSERM U1081, Faculté de Médecine, Université Côte d’Azur, 06107 Nice, France
| | - Véronique Paquis-Flucklinger
- Service de Génétique Médicale, Hôpital l’Archet 2, CHU de Nice, 151 Route Saint-Antoine de Ginestière, 06202 Nice, France; (M.S.); (M.P.); (A.C.); (V.P.-F.); (S.A.-E.-M.S.)
- CNRS UMR7284/ INSERM U1081, Faculté de Médecine, Université Côte d’Azur, 06107 Nice, France
| | - Samira Ait-El-Mkadem Saadi
- Service de Génétique Médicale, Hôpital l’Archet 2, CHU de Nice, 151 Route Saint-Antoine de Ginestière, 06202 Nice, France; (M.S.); (M.P.); (A.C.); (V.P.-F.); (S.A.-E.-M.S.)
- CNRS UMR7284/ INSERM U1081, Faculté de Médecine, Université Côte d’Azur, 06107 Nice, France
| | - Cécile Rouzier
- Service de Génétique Médicale, Hôpital l’Archet 2, CHU de Nice, 151 Route Saint-Antoine de Ginestière, 06202 Nice, France; (M.S.); (M.P.); (A.C.); (V.P.-F.); (S.A.-E.-M.S.)
- CNRS UMR7284/ INSERM U1081, Faculté de Médecine, Université Côte d’Azur, 06107 Nice, France
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Teive HA, Coutinho L, Meira AT, Franklin GL, Camargo CHF, Munhoz RP. Autosomal Recessive Cerebellar Ataxias: New Acronyms, Old Eponyms, and the Butterfly Life Cycle. Mov Disord Clin Pract 2023; 10:1297-1301. [PMID: 37772306 PMCID: PMC10525046 DOI: 10.1002/mdc3.13835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 06/14/2023] [Accepted: 06/26/2023] [Indexed: 09/30/2023] Open
Affiliation(s)
- Hélio A.G. Teive
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de ClínicasFederal University of ParanáCuritibaParanáBrazil
- Neurological Diseases Group, Graduate Program in Internal Medicine, Internal Medicine Department, Hospital de ClínicasFederal University of ParanáCuritibaParanáBrazil
| | - Léo Coutinho
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de ClínicasFederal University of ParanáCuritibaParanáBrazil
| | - Alex T. Meira
- Movement Disorders Unit, Neurology Service, Internal Medicine DepartmentFederal University of ParaíbaJoão PessoaParaíbaBrazil
| | - Gustavo L. Franklin
- Internal Medicine DepartmentPontifical Catholic University of ParanáCuritibaParanáBrazil
| | - Carlos Henrique F. Camargo
- Neurological Diseases Group, Graduate Program in Internal Medicine, Internal Medicine Department, Hospital de ClínicasFederal University of ParanáCuritibaParanáBrazil
| | - Renato Puppi Munhoz
- Division of NeurologyUniversity of Toronto, Toronto Western Hospital–University Health Network, Morton and Gloria Shulman Movement Disorders Centre and Edmond J. Safra Program in Parkinson's DiseaseTorontoOntarioCanada
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23
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Spagnolo F, Monfrini E, Pinto V, Di Maggio G, De Marco P, Comi GP, Rini A, Di Fonzo A. Tremulous spastic ataxia in a patient with a homozygous truncating SYNE1 variant. Clin Park Relat Disord 2023; 9:100205. [PMID: 37388713 PMCID: PMC10300247 DOI: 10.1016/j.prdoa.2023.100205] [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: 11/20/2022] [Revised: 05/14/2023] [Accepted: 06/02/2023] [Indexed: 07/01/2023] Open
Abstract
We describe a case of severe adult-onset progressive tremulous cerebellar ataxia with pyramidal signs associated with a rare homozygous truncating pathogenic variant in the SYNE1 gene (p.Arg5371*). This contrasts the initial views on SYNE1-related ataxia as a relatively benign, slowly progressive condition, with important implications for clinic-genetic counselling.
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Affiliation(s)
| | - Edoardo Monfrini
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy
| | - Vincenza Pinto
- Neurological Department, A. Perrino's Hospital, Brindisi, Italy
| | | | - Paolo De Marco
- Neurological Department, A. Perrino's Hospital, Brindisi, Italy
| | - Giacomo P. Comi
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy
| | - Augusto Rini
- Neurological Department, A. Perrino's Hospital, Brindisi, Italy
| | - Alessio Di Fonzo
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy
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24
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Yoshida Y, Uchida K, Kodo K, Ishizaki-Asami R, Maeda J, Katsumata Y, Yuasa S, Fukuda K, Kosaki K, Watanabe Y, Nakagawa O, Yamagishi H. A genetic and developmental biological approach for a family with complex congenital heart diseases-evidence of digenic inheritance. Front Cardiovasc Med 2023; 10:1135141. [PMID: 37180804 PMCID: PMC10166836 DOI: 10.3389/fcvm.2023.1135141] [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: 12/31/2022] [Accepted: 04/10/2023] [Indexed: 05/16/2023] Open
Abstract
Objective Congenital heart disease (CHD) is caused by cardiovascular developmental defects and has a global prevalence of ∼1%. The etiology of CHD is multifactorial and remains generally unknown, despite advances in analytical techniques based on next-generation sequencing (NGS). The aim of our study was to elucidate the multi-genetic origin and pathogenesis of an intriguing familial case with complex CHD. Methods We performed an original trio-based gene panel analysis using NGS of the family, including two siblings with CHD of single ventricular phenotype, and their unaffected parents. The pathogenicity of the detected rare variants was investigated in silico, and the functional effects of the variants were confirmed in vitro using luciferase assays. The combinatorial effect of gene alterations of the putative responsible genes was tested in vivo using genetically engineered mutant mice. Results NGS-based gene panel analyses revealed two heterozygous rare variants in NODAL and in TBX20 common to the siblings and to just one of parents. Both variants were suspected pathogenic in silico, and decreased transcriptional activities of downstream signaling pathways were observed in vitro. The analyses of Nodal and Tbx20 double mutant mice demonstrated that Nodal+/-Tbx20-/- embryos showed more severe defects than Nodal+/+Tbx20-/- embryos during early heart development. The expression of Pitx2, a known downstream target of Nodal, was downregulated in Tbx20-/- mutants. Conclusions Two rare variants on NODAL and TBX20 genes detected in this family were considered to be loss-of-function mutations. Our results suggest that NODAL and TBX20 may be complementary for the cardiac development, and a combinatorial loss-of-function of NODAL and TBX20 could be implicated in digenic inherence as the etiology of complex CHD associated with single ventricle defects in this family.
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Affiliation(s)
- Yu Yoshida
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Keiko Uchida
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
- Health Center, Keio University, Kanagawa, Japan
| | - Kazuki Kodo
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | | | - Jun Maeda
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | | | - Shinsuke Yuasa
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Keiichi Fukuda
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Yusuke Watanabe
- Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Osamu Nakagawa
- Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Hiroyuki Yamagishi
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
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25
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Saito R, Hara N, Tada M, Wakabayashi M, Miyashita A, Nishizawa M, Onodera O, Ikeuchi T, Kakita A. SYNE1-ataxia: clinicopathologic features of an autopsied patient with novel compound heterozygous mutations. J Neuropathol Exp Neurol 2023; 82:267-271. [PMID: 36525394 DOI: 10.1093/jnen/nlac120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- Rie Saito
- Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Norikazu Hara
- Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan
| | - Mari Tada
- Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan
| | | | - Akinori Miyashita
- Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masatoyo Nishizawa
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Osamu Onodera
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Takeshi Ikeuchi
- Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan
| | - Akiyoshi Kakita
- Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan
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26
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Cubilla M, Papazoglu G, Asteggiano C. Dystroglycanopathies: Genetic Bases of Muscular Dystrophies Due to Alteration in the O-Glycosylation of α-Dystroglycan. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2023; 11. [DOI: 10.1590/2326-4594-jiems-2022-0005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Affiliation(s)
- M.A. Cubilla
- Hospital de Niños de la Santísima Trinidad, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina
| | - G.M. Papazoglu
- Hospital de Niños de la Santísima Trinidad, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina
| | - C.G. Asteggiano
- Hospital de Niños de la Santísima Trinidad, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina; Universidad Católica de Córdoba, Argentina
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27
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A family-based study of genetic and epigenetic effects across multiple neurocognitive, motor, social-cognitive and social-behavioral functions. Behav Brain Funct 2022; 18:14. [PMID: 36457050 PMCID: PMC9714039 DOI: 10.1186/s12993-022-00198-0] [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: 02/24/2022] [Accepted: 09/09/2022] [Indexed: 12/03/2022] Open
Abstract
Many psychiatric and neurodevelopmental disorders are known to be heritable, but studies trying to elucidate the genetic architecture of such traits often lag behind studies of somatic traits and diseases. The reasons as to why relatively few genome-wide significant associations have been reported for such traits have to do with the sample sizes needed for the detection of small effects, the difficulty in defining and characterizing the phenotypes, partially due to overlaps in affected underlying domains (which is especially true for cognitive phenotypes), and the complex genetic architectures of the phenotypes, which are not wholly captured in traditional case-control GWAS designs. We aimed to tackle the last two issues by performing GWASs of eight quantitative neurocognitive, motor, social-cognitive and social-behavioral traits, which may be considered endophenotypes for a variety of psychiatric and neurodevelopmental conditions, and for which we employed models capturing both general genetic association and parent-of-origin effects, in a family-based sample comprising 402 children and their parents (mostly family trios). We identified 48 genome-wide significant associations across several traits, of which 3 also survived our strict study-wide quality criteria. We additionally performed a functional annotation of implicated genes, as most of the 48 associations were with variants within protein-coding genes. In total, our study highlighted associations with five genes (TGM3, CACNB4, ANKS1B, CSMD1 and SYNE1) associated with measures of working memory, processing speed and social behavior. Our results thus identify novel associations, including previously unreported parent-of-origin associations with relevant genes, and our top results illustrate new potential gene → endophenotype → disorder pathways.
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28
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Fischer NC, Friedman V, Martinez-Reyes MA, Hao H, Chowdhury TA, Starr DA, Quinn CC. The ANC-1 (Nesprin-1/2) organelle-anchoring protein functions through mitochondria to polarize axon growth in response to SLT-1. PLoS Genet 2022; 18:e1010521. [PMID: 36409768 PMCID: PMC9721489 DOI: 10.1371/journal.pgen.1010521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 12/05/2022] [Accepted: 11/11/2022] [Indexed: 11/22/2022] Open
Abstract
A family of giant KASH proteins, including C. elegans ANC-1 and mammalian Nesprin-1 and -2, are involved in organelle anchoring and are associated with multiple neurodevelopmental disorders including autism, bipolar disorder, and schizophrenia. However, little is known about how these proteins function in neurons. Moreover, the role of organelle anchoring in axon development is poorly understood. Here, we report that ANC-1 functions with the SLT-1 extracellular guidance cue to polarize ALM axon growth. This role for ANC-1 is specific to its longer ANC-1A and ANC-1C isoforms, suggesting that it is mechanistically distinct from previously described roles for ANC-1. We find that ANC-1 is required for the localization of a cluster of mitochondria to the base of the proximal axon. Furthermore, genetic and pharmacological studies indicate that ANC-1 functions with mitochondria to promote polarization of ALM axon growth. These observations reveal a mechanism whereby ANC-1 functions through mitochondria to polarize axon growth in response to SLT-1.
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Affiliation(s)
- Nathan C. Fischer
- Department of Biological Sciences, University of Wisconsin-Milwaukee; Milwaukee, Wisconsin, United States of America
| | - Vladislav Friedman
- Department of Biological Sciences, University of Wisconsin-Milwaukee; Milwaukee, Wisconsin, United States of America
| | - Miguel A. Martinez-Reyes
- Department of Biological Sciences, University of Wisconsin-Milwaukee; Milwaukee, Wisconsin, United States of America
| | - Hongyan Hao
- Department of Molecular and Cellular Biology, University of California, Davis, California, United States of America
| | - Tamjid A. Chowdhury
- Department of Biological Sciences, University of Wisconsin-Milwaukee; Milwaukee, Wisconsin, United States of America
| | - Daniel A. Starr
- Department of Molecular and Cellular Biology, University of California, Davis, California, United States of America
| | - Christopher C. Quinn
- Department of Biological Sciences, University of Wisconsin-Milwaukee; Milwaukee, Wisconsin, United States of America
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29
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Leong EL, Khaing NT, Cadot B, Hong WL, Kozlov S, Werner H, Wong ESM, Stewart CL, Burke B, Lee YL. Nesprin-1 LINC complexes recruit microtubule cytoskeleton proteins and drive pathology in Lmna-mutant striated muscle. Hum Mol Genet 2022; 32:177-191. [PMID: 35925868 PMCID: PMC9840208 DOI: 10.1093/hmg/ddac179] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 01/19/2023] Open
Abstract
Mutations in LMNA, the gene encoding A-type lamins, cause laminopathies-diseases of striated muscle and other tissues. The aetiology of laminopathies has been attributed to perturbation of chromatin organization or structural weakening of the nuclear envelope (NE) such that the nucleus becomes more prone to mechanical damage. The latter model requires a conduit for force transmission to the nucleus. NE-associated Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes are one such pathway. Using clustered regularly interspaced short palindromic repeats to disrupt the Nesprin-1 KASH (Klarsicht, ANC-1, Syne Homology) domain, we identified this LINC complex protein as the predominant NE anchor for microtubule cytoskeleton components, including nucleation activities and motor complexes, in mouse cardiomyocytes. Loss of Nesprin-1 LINC complexes resulted in loss of microtubule cytoskeleton proteins at the nucleus and changes in nuclear morphology and positioning in striated muscle cells, but with no overt physiological defects. Disrupting the KASH domain of Nesprin-1 suppresses Lmna-linked cardiac pathology, likely by reducing microtubule cytoskeleton activities at the nucleus. Nesprin-1 LINC complexes thus represent a potential therapeutic target for striated muscle laminopathies.
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Affiliation(s)
| | | | - Bruno Cadot
- Sorbonne Université, INSERM U974, Institut de Myologie, GH Pitié Salpêtrière, 47 Boulevard de l’Hôpital, Paris 75013, France
| | - Wei Liang Hong
- Institute of Medical Biology, Agency for Science Technology and Research (ASTAR), 8A Biomedical Grove, Level 6 Immunos, Singapore 138648, Singapore,ASTAR Skin Research Labs (ASRL), Agency for Science Technology and Research (ASTAR), 8A Biomedical Grove, Level 6 Immunos, Singapore 138648, Singapore
| | - Serguei Kozlov
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Hendrikje Werner
- Institute of Medical Biology, Agency for Science Technology and Research (ASTAR), 8A Biomedical Grove, Level 6 Immunos, Singapore 138648, Singapore,ASTAR Skin Research Labs (ASRL), Agency for Science Technology and Research (ASTAR), 8A Biomedical Grove, Level 6 Immunos, Singapore 138648, Singapore
| | - Esther Sook Miin Wong
- Institute of Medical Biology, Agency for Science Technology and Research (ASTAR), 8A Biomedical Grove, Level 6 Immunos, Singapore 138648, Singapore,Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), 8A Biomedical Grove, Level 5 Immunos, Singapore 138648, Singapore
| | - Colin L Stewart
- To whom correspondence should be addressed. Colin L. Stewart, ; Brian Burke, ; Yin Loon Lee,
| | - Brian Burke
- To whom correspondence should be addressed. Colin L. Stewart, ; Brian Burke, ; Yin Loon Lee,
| | - Yin Loon Lee
- To whom correspondence should be addressed. Colin L. Stewart, ; Brian Burke, ; Yin Loon Lee,
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30
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A Nuclear Belt Fastens on Neural Cell Fate. Cells 2022; 11:cells11111761. [PMID: 35681456 PMCID: PMC9179901 DOI: 10.3390/cells11111761] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/20/2022] [Accepted: 05/21/2022] [Indexed: 12/22/2022] Open
Abstract
Successful embryonic and adult neurogenesis require proliferating neural stem and progenitor cells that are intrinsically and extrinsically guided into a neuronal fate. In turn, migration of new-born neurons underlies the complex cytoarchitecture of the brain. Proliferation and migration are therefore essential for brain development, homeostasis and function in adulthood. Among several tightly regulated processes involved in brain formation and function, recent evidence points to the nuclear envelope (NE) and NE-associated components as critical new contributors. Classically, the NE was thought to merely represent a barrier mediating selective exchange between the cytoplasm and nucleoplasm. However, research over the past two decades has highlighted more sophisticated and diverse roles for NE components in progenitor fate choice and migration of their progeny by tuning gene expression via interactions with chromatin, transcription factors and epigenetic factors. Defects in NE components lead to neurodevelopmental impairments, whereas age-related changes in NE components are proposed to influence neurodegenerative diseases. Thus, understanding the roles of NE components in brain development, maintenance and aging is likely to reveal new pathophysiological mechanisms for intervention. Here, we review recent findings for the previously underrepresented contribution of the NE in neuronal commitment and migration, and envision future avenues for investigation.
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31
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Arias M, Mir P, Fernández-Matarrubia M, Arpa J, García-Ramos R, Blanco-Arias P, Quintans B, Sobrido MJ. Autosomal recessive spinocerebellar ataxia SCAR8/ARCA1: first families detected in Spain. NEUROLOGÍA (ENGLISH EDITION) 2022; 37:257-262. [PMID: 35595401 DOI: 10.1016/j.nrleng.2019.01.014] [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: 12/28/2018] [Accepted: 01/16/2019] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Autosomal recessive spinocerebellar ataxia type 8 (ARCA1/SCAR8) is caused by mutations of the SYNE1 gene. The disease was initially described in families from Quebec (Canada) with a phenotype of pure cerebellar syndrome, but in recent years has been reported with a more variable clinical phenotype in other countries. Cases have recently been described of muscular dystrophy, arthrogryposis, and cardiomyopathy due to SYNE1 mutations. OBJECTIVE To describe clinical and molecular findings from 4 patients (3 men and one woman) diagnosed with ARCA1/SCAR8 from 3 Spanish families from different regions. MATERIAL AND METHODS We describe the clinical, paraclinical, and genetic results from 4 patients diagnosed with ARCA1/SCAR8 at different Spanish neurology departments. RESULTS Onset occurred in the third or fourth decade of life in all patients. After 15 years of progression, 3 patients presented pure cerebellar syndrome, similar to the Canadian patients; the fourth patient, with over 30 years' progression, presented vertical gaze palsy, pyramidal signs, and moderate cognitive impairment. In all patients, MRI studies showed cerebellar atrophy. The genetic study revealed distinct pathogenic SYNE1 mutations in each family. CONCLUSIONS ARCA1/SCAR8 can be found worldwide and may be caused by many distinct mutations in the SYNE1 gene. The disease may manifest with a complex phenotype of varying severity.
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Affiliation(s)
- M Arias
- Servicio de Neurología, Complexo Hospitalario de Santiago de Compostela, Santiago de Compostela, La Coruña, Spain.
| | - P Mir
- Servicio de Neurología, Hospital Virgen del Rocío, Sevilla, Spain
| | | | - J Arpa
- Servicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain
| | - R García-Ramos
- Servicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain
| | - P Blanco-Arias
- Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, La Coruña, Spain
| | - B Quintans
- Grupo de Neurogenética, Instituto de Investigación Sanitaria de Santiago (IDIS)-Complexo Hospitalario Universitario, Santiago de Compostela, La Coruña, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - M J Sobrido
- Grupo de Neurogenética, Instituto de Investigación Sanitaria de Santiago (IDIS)-Complexo Hospitalario Universitario, Santiago de Compostela, La Coruña, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
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32
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Arias M, Mir P, Fernández-Matarrubia M, Arpa J, García-Ramos R, Blanco-Arias P, Quintans B, Sobrido MJ. Autosomal recessive spinocerebellar ataxia SCAR8/ARCA1: First families detected in Spain. Neurologia 2022; 37:257-262. [PMID: 31103315 DOI: 10.1016/j.nrl.2019.01.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 01/16/2019] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION Autosomal recessive spinocerebellar ataxia type 8 (ARCA1/SCAR8) is caused by mutations of the SYNE1 gene. The disease was initially described in families from Quebec (Canada) with a phenotype of pure cerebellar syndrome, but in recent years has been reported with a more variable clinical phenotype in other countries. Cases have recently been described of muscular dystrophy, arthrogryposis, and cardiomyopathy due to SYNE1 mutations. OBJECTIVE To describe clinical and molecular findings from 4 patients (3 men and one woman) diagnosed with ARCA1/SCAR8 from 3 Spanish families from different regions. MATERIAL AND METHODS We describe the clinical, paraclinical, and genetic results from 4 patients diagnosed with ARCA1/SCAR8 at different Spanish neurology departments. RESULTS Onset occurred in the third or fourth decade of live in all patients. After 15 years of progression, 3 patients presented pure cerebellar syndrome, similar to the Canadian patients; the fourth patient, with over 30 years' progression, presented vertical gaze palsy, pyramidal signs, and moderate cognitive impairment. In all patients, MRI studies showed cerebellar atrophy. The genetic study revealed distinct pathogenic SYNE1 mutations in each family. CONCLUSIONS ARCA1/SCAR8 can be found worldwide and may be caused by many distinct mutations in the SYNE1 gene. The disease may manifest with a complex phenotype of varying severity.
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Affiliation(s)
- M Arias
- Servicio de Neurología, Complexo Hospitalario de Santiago de Compostela, Santiago de Compostela, La Coruña, España.
| | - P Mir
- Servicio de Neurología, Hospital Virgen del Rocío, Sevilla, España
| | | | - J Arpa
- Servicio de Neurología, Hospital Clínico San Carlos de, Madrid, España
| | - R García-Ramos
- Servicio de Neurología, Hospital Clínico San Carlos de, Madrid, España
| | - P Blanco-Arias
- Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, La Coruña, España
| | - B Quintans
- Grupo de Neurogenética, Instituto de Investigación Sanitaria de Santiago (IDIS)-Complexo Hospitalario Universitario, Santiago de Compostela, La Coruña, España; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, España
| | - M J Sobrido
- Grupo de Neurogenética, Instituto de Investigación Sanitaria de Santiago (IDIS)-Complexo Hospitalario Universitario, Santiago de Compostela, La Coruña, España; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, España
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33
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Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia. Cells 2022; 11:cells11060981. [PMID: 35326432 PMCID: PMC8946949 DOI: 10.3390/cells11060981] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 01/02/2023] Open
Abstract
Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (SACS and KIF1C) and with ataxia and neuropathy or AOA (PNKP). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in KIF1A, CACNA1A, or ATP1A3, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.
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34
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Qian N, Wei T, Yang W, Wang J, Zhang S, Jin S, Dong W, Hao W, Yang Y, Huang R. Case Report: Late-Onset Autosomal Recessive Cerebellar Ataxia Associated With SYNE1 Mutation in a Chinese Family. Front Genet 2022; 13:795188. [PMID: 35281832 PMCID: PMC8905644 DOI: 10.3389/fgene.2022.795188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
Autosomal recessive cerebellar ataxia type 1 (ARCA-1), also known as autosomal recessive spinocerebellar ataxia type 8 (SCAR8), is caused by spectrin repeat containing nuclear envelope protein 1 (SYNE1) gene mutation. Nesprin-1, encoded by SYNE1, is widely expressed in various tissues, especially in the striated muscle and cerebellum. The destruction of Nesprin-1 is related to neuronal and neuromuscular lesions. It has been reported that SYNE1 gene variation is associated with Emery-Dreifuss muscular dystrophy type 4, arthrogryposis multiplex congenita, SCAR8, and dilated cardiomyopathy. The clinical manifestations of SCAR8 are mainly characterized by relatively pure cerebellar ataxia and may be accompanied by upper and/or lower motor neuron dysfunction. Some affected people may also display cerebellar cognitive affective syndrome. It is conventionally held that the age at the onset of SCAR8 is between 6 and 42 years (the median age is 17 years). Here, we report a pedigree with SCAR8 where the onset age in the proband is 48 years. This case report extends the genetic profile and clinical features of SCAR8. A new pathogenic site (c.7578del; p.S2526Sfs*8) located in SYNE1, which is the genetic cause of the patient, was identified via whole exome sequencing (WES).
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Affiliation(s)
- Nannan Qian
- Graduate School, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Taohua Wei
- The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Wenming Yang
- The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
- Key Laboratory of Xin’an Medicine Ministry of Education, Hefei, China
| | - Jiuxiang Wang
- The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Shijie Zhang
- The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Shan Jin
- The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Wei Dong
- Graduate School, Anhui University of Traditional Chinese Medicine, Hefei, China
- The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Wenjie Hao
- Graduate School, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Yue Yang
- Graduate School, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Ru Huang
- V-Medical Laboratory Co., Ltd, Hangzhou, China
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35
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Abstract
The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. Laminopathies are diseases caused by mutations in genes encoding protein components of the lamina and these other nuclear envelope substructures. Mutations in the single gene encoding lamin A and C, which are expressed in most differentiated somatic cells, cause diseases affecting striated muscle, adipose tissue, peripheral nerve, and multiple systems with features of accelerated aging. Mutations in genes encoding other nuclear envelope proteins also cause an array of diseases that selectively affect different tissues or organs. In some instances, the molecular and cellular consequences of laminopathy-causing mutations are known. However, even when these are understood, mechanisms explaining specific tissue or organ pathology remain enigmatic. Current mechanistic hypotheses focus on how alterations in the nuclear envelope may affect gene expression, including via the regulation of signaling pathways, or cellular mechanics, including responses to mechanical stress.
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Affiliation(s)
- Ji-Yeon Shin
- Department of Medicine and Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Howard J. Worman
- Department of Medicine and Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
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36
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Padilla-Mejia NE, Makarov AA, Barlow LD, Butterfield ER, Field MC. Evolution and diversification of the nuclear envelope. Nucleus 2021; 12:21-41. [PMID: 33435791 PMCID: PMC7889174 DOI: 10.1080/19491034.2021.1874135] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/08/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023] Open
Abstract
Eukaryotic cells arose ~1.5 billion years ago, with the endomembrane system a central feature, facilitating evolution of intracellular compartments. Endomembranes include the nuclear envelope (NE) dividing the cytoplasm and nucleoplasm. The NE possesses universal features: a double lipid bilayer membrane, nuclear pore complexes (NPCs), and continuity with the endoplasmic reticulum, indicating common evolutionary origin. However, levels of specialization between lineages remains unclear, despite distinct mechanisms underpinning various nuclear activities. Several distinct modes of molecular evolution facilitate organellar diversification and to understand which apply to the NE, we exploited proteomic datasets of purified nuclear envelopes from model systems for comparative analysis. We find enrichment of core nuclear functions amongst the widely conserved proteins to be less numerous than lineage-specific cohorts, but enriched in core nuclear functions. This, together with consideration of additional evidence, suggests that, despite a common origin, the NE has evolved as a highly diverse organelle with significant lineage-specific functionality.
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Affiliation(s)
- Norma E. Padilla-Mejia
- Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK
| | - Alexandr A. Makarov
- Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK
| | - Lael D. Barlow
- Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK
| | - Erin R. Butterfield
- Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK
| | - Mark C. Field
- Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České, Czech Republic
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37
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Dragašević-Mišković N, Stanković I, Milovanović A, Kostić VS. Autosomal recessive adult onset ataxia. J Neurol 2021; 269:504-533. [PMID: 34499204 DOI: 10.1007/s00415-021-10763-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 11/24/2022]
Abstract
Autosomal recessive ataxias (ARCA) represent a complex group of diseases ranging from primary ataxias to rare and complex metabolic disorders in which ataxia is a part of the clinical picture. Small number of ARCA manifest exclusively in adulthood, while majority of typical childhood onset ARCA may also start later with atypical clinical presentation. We have systematically searched the literature for ARCA with adult onset, both in the group of primary ataxias including those that are less frequently described in isolated or in a small number of families, and also in the group of complex and metabolic diseases in which ataxia is only part of the clinical picture. We propose an algorithm that could be used when encountering a patient with adult onset sporadic or recessive ataxia in whom the acquired causes are excluded. ARCA are frequently neglected in the differential diagnosis of adult-onset ataxias. Rising awareness of their clinical significance is important, not only because some of these disorders may be potentially treatable, but also for prognostic implications and inclusion of patients to future clinical trials with disease modifying agents.
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Affiliation(s)
- Nataša Dragašević-Mišković
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia.
| | - Iva Stanković
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia
| | - Andona Milovanović
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia
| | - Vladimir S Kostić
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia
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38
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Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism. Genes (Basel) 2021; 12:genes12091294. [PMID: 34573277 PMCID: PMC8470961 DOI: 10.3390/genes12091294] [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: 06/30/2021] [Revised: 08/06/2021] [Accepted: 08/20/2021] [Indexed: 12/20/2022] Open
Abstract
Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by investigating potential associations with SYNE2 mutations. Specifically, the disease-causing variants of SYNE2 in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of SYNE2 (NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells. SYNE2 transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic SYNE2 mutations may be a new cause of intellectual disability and ASD.
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Kos MZ, Carless MA, Blondell L, Leland MM, Knape KD, Göring HHH, Szabó CÁ. Whole Genome Sequence Data From Captive Baboons Implicate RBFOX1 in Epileptic Seizure Risk. Front Genet 2021; 12:714282. [PMID: 34490042 PMCID: PMC8417722 DOI: 10.3389/fgene.2021.714282] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/27/2021] [Indexed: 01/18/2023] Open
Abstract
In this study, we investigate the genetic determinants that underlie epilepsy in a captive baboon pedigree and evaluate the potential suitability of this non-human primate model for understanding the genetic etiology of human epilepsy. Archived whole-genome sequence data were analyzed using both a candidate gene approach that targeted variants in baboon homologs of 19 genes (n = 20,881 SNPs) previously implicated in genetic generalized epilepsy (GGE) and a more agnostic approach that examined protein-altering mutations genome-wide as assessed by snpEff (n = 36,169). Measured genotype association tests for baboon cases of epileptic seizure were performed using SOLAR, as well as gene set enrichment analyses (GSEA) and protein-protein interaction (PPI) network construction of top association hits genome-wide (p < 0.01; n = 441 genes). The maximum likelihood estimate of heritability for epileptic seizure in the pedigreed baboon sample is 0.76 (SE = 0.77; p = 0.07). Among candidate genes for GGE, a significant association was detected for an intronic SNP in RBFOX1 (p = 5.92 × 10-6; adjusted p = 0.016). For protein-altering variants, no genome-wide significant results were observed for epilepsy status. However, GSEA revealed significant positive enrichment for genes involved in the extracellular matrix structure (ECM; FDR = 0.0072) and collagen formation (FDR = 0.017), which was reflected in a major PPI network cluster. This preliminary study highlights the potential role of RBFOX1 in the epileptic baboon, a protein involved in transcriptomic regulation of multiple epilepsy candidate genes in humans and itself previously implicated in human epilepsy, both focal and generalized. Moreover, protein-damaging variants from across the genome exhibit a pattern of association that links collagen-containing ECM to epilepsy risk. These findings suggest a shared genetic etiology between baboon and human forms of GGE and lay the foundation for follow-up research.
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Affiliation(s)
- Mark Z. Kos
- Department of Human Genetics, South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, United States
| | - Melanie A. Carless
- Department of Biology, The University of Texas at San Antonio, San Antonio, TX, United States
- Brain Health Consortium, The University of Texas at San Antonio, San Antonio, TX, United States
| | - Lucy Blondell
- Department of Human Genetics, South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, United States
| | - M. Michelle Leland
- Laboratory Animal Research, UT Health San Antonio, San Antonio, TX, United States
| | - Koyle D. Knape
- Department of Neurology, UT Health San Antonio, San Antonio, TX, United States
| | - Harald H. H. Göring
- Department of Human Genetics, South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, United States
| | - Charles Ákos Szabó
- Department of Neurology, UT Health San Antonio, San Antonio, TX, United States
- South Texas Comprehensive Epilepsy Center, San Antonio, TX, United States
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40
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Karlsson WK, Højgaard JLS, Vilhelmsen A, Crone C, Andersen B, Law I, Møller LB, Nielsen TT, Nielsen EN, Krag T, Svenstrup K, Nielsen JE. Novel Homozygous Truncating Variant Widens the Spectrum of Early-Onset Multisystemic SYNE1 Ataxia. THE CEREBELLUM 2021; 21:514-519. [PMID: 34318393 DOI: 10.1007/s12311-021-01308-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/16/2021] [Indexed: 11/28/2022]
Abstract
Pathogenic variants in the SYNE1 gene are associated with a phenotypic spectrum spanning from late-onset, slowly progressive, relatively pure ataxia to early-onset, fast progressive multisystemic disease. Since its first description in 2007 as an adult-onset ataxia in French Canadian families, subsequent identification of patients worldwide has widened the clinical spectrum and increased the number of identified pathogenic variants. We report a 20-year-old Faroese female with early-onset progressive gait problems, weakness, dysphagia, slurred speech, orthostatic dizziness, and urge incontinence. Neurological examination revealed mild cognitive deficits, dysarthria, broken slow pursuit, hypometric saccades, weakness with spasticity, hyperreflexia, absent ankle reflexes, ataxia, and wide-based, spastic gait. Magnetic resonance imaging displayed atrophy of the cerebellum, brainstem, and spinal cord. Severely prolonged central motor conduction time and lower motor neuron involvement was demonstrated electrophysiologically. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism of the cerebellum and right frontal lobe. Muscle biopsy revealed chronic neurogenic changes and near-absent immunostaining for Nesprin-1. Next-generation sequencing revealed a previously undescribed homozygous truncating, likely pathogenic variant in the SYNE1 gene. The patient's mother and paternal grandfather were heterozygous carriers of the variant. Her father's genotype was unobtainable. We expand the list of likely pathogenic variants in SYNE1 ataxia with a novel homozygous truncating variant with proximity to the C-terminus and relate it to a phenotype comprising early-onset cerebellar deficits, upper and lower motor neuron involvement and cognitive deficits. Also, we report novel findings of focally reduced frontal lobe FDG-PET uptake and motor evoked potential abnormalities suggestive of central demyelination.
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Affiliation(s)
- William Kristian Karlsson
- Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark.
| | - Joan Lilja Sunnleyg Højgaard
- Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark
| | - Anna Vilhelmsen
- Department of Psychiatry, National Hospital of the Faroe Islands, Tórshavn, Faroe Islands
| | - Clarissa Crone
- Department of Neurophysiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Birgit Andersen
- Department of Neurophysiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ian Law
- Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lisbeth Birk Møller
- Department of Clinical Genetics, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark
| | - Troels Tolstrup Nielsen
- Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark.,Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Emilie Neerup Nielsen
- Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark
| | - Thomas Krag
- Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark.,Department of Neurology, Copenhagen Neuromuscular Center, University of Copenhagen, Copenhagen, Denmark
| | - Kirsten Svenstrup
- Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark.,Department of Neurology, Copenhagen Neuromuscular Center, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen Erik Nielsen
- Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark.,Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
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41
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Holla VV, Surisetti BK, Prasad S, Pal PK. Focal dystonia in a case of SYNE1 spastic-ataxia: Expanding the phenotypic spectrum. Parkinsonism Relat Disord 2021; 87:22-24. [PMID: 33933852 DOI: 10.1016/j.parkreldis.2021.04.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 04/02/2021] [Accepted: 04/11/2021] [Indexed: 11/24/2022]
Abstract
Synaptic nuclear envelope protein-1 (SYNE1) related cerebellar ataxia also called ARCA1 or SCAR8, manifests as a relatively pure cerebellar ataxia or with additional neurological involvement. Dystonia is rarely seen in SYNE1 ataxia and to the best of our knowledge, there are only three reports of dystonia in patients with SYNE1 ataxia. This report describes a 22-year-old woman with chronic progressive spastic-ataxia of 3-year duration with additional focal dystonia of the right upper limb. Patient had cerebellar atrophy on MRI brain and a novel pathogenic homozygous variant in exon 74 of the SYNE1 gene (p.Gln4047Ter).
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Affiliation(s)
- Vikram V Holla
- Department of Neurology, National Institute of Mental Health & Neurosciences, Hosur Road, Bengaluru, 560029, Karnataka, India
| | - Bharath Kumar Surisetti
- Department of Neurology, National Institute of Mental Health & Neurosciences, Hosur Road, Bengaluru, 560029, Karnataka, India
| | - Shweta Prasad
- Department of Neurology, National Institute of Mental Health & Neurosciences, Hosur Road, Bengaluru, 560029, Karnataka, India; Department of Clinical Neurosciences, National Institute of Mental Health & Neurosciences, Hosur Road, Bengaluru, 560029, Karnataka, India
| | - Pramod Kumar Pal
- Department of Neurology, National Institute of Mental Health & Neurosciences, Hosur Road, Bengaluru, 560029, Karnataka, India.
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42
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Valentina Castillo J, Catherine Díaz S, Bustamante ML, Ferreira MG, Teive HAG, Miranda M. Autosomal Recessive Cerebellar Ataxia 1: First Case Report Depicting a Variant in SYNE1 Gene in a Chilean Patient. THE CEREBELLUM 2021; 20:938-941. [PMID: 33651373 DOI: 10.1007/s12311-021-01250-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/22/2021] [Indexed: 10/22/2022]
Abstract
Autosomal recessive cerebellar ataxia type 1 (ARCA-1) or spinocerebellar ataxia autosomal recessive type 8 (SCAR8) is a slowly progressive neurodegenerative disorder that occurs due to mutations in the spectrin repeat containing nuclear envelope protein 1 (SYNE1) gene. Previously considered a rare cause of ARCA, related to French-Canadian patients from Beauce, Quebec, Canada, SYNE1 ataxia is now known to be of worldwide distribution. We present the case report of a 54-year-old male patient with the genetic diagnosis of SYNE1 ataxia, presenting with a SYNE1 gene mutation never described in Chilean population before.
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Affiliation(s)
- J Valentina Castillo
- Clinical Genetics Resident, Clinical Genetics Department, Clinical Hospital of the University of Chile, Santiago, Chile
| | - S Catherine Díaz
- Head of Genetics Unit, Roberto del Río Hospital, Genetics Section, 1085, Independencia, Santiago, Chile. .,Fundación Diagnosis, Santiago, Chile.
| | - María Leonor Bustamante
- Fundación Diagnosis, Santiago, Chile.,Human Genetics Program, Institute of Biomedical Sciences, School of Medicine, University of Chile, Santiago, Chile.,Department of Psychiatry and Mental Health, North Campus, School of Medicine, University of Chile, Santiago, Chile
| | - Matheus Gomes Ferreira
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, PR, Brazil
| | - Hélio A G Teive
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, PR, Brazil
| | - Marcelo Miranda
- Fundación Diagnosis, Santiago, Chile.,Neurology Unit, Las Condes Clinic, Santiago, Chile
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43
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Szpisjak L, Szaraz G, Salamon A, Nemeth VL, Szepfalusi N, Veres G, Kincses B, Maroti Z, Kalmar T, Rydzanicz M, Ploski R, Klivenyi P, Zadori D. Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study. BMC Neurosci 2021; 22:7. [PMID: 33526008 PMCID: PMC7852103 DOI: 10.1186/s12868-021-00612-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 01/13/2021] [Indexed: 11/11/2022] Open
Abstract
Background SYNE1 ataxia is an autosomal recessive hereditary condition, the main characteristic features of which are gait and limb ataxia and cerebellar dysarthria. Reports have revealed that the clinical phenotype of SYNE1 ataxia is more complex than the first published cases with pure cerebellar signs indicated. The aim of this study was to characterize eye movement alterations in the first diagnosed Hungarian SYNE1 ataxia patients. Results Saccades and antisaccades were examined with an eye tracker device in 3 SYNE1 (one patient has two frameshift mutations [c.8515_8516insA, p.Met2839Asnfs*53 and c.11594_11595insG, p.Glu3866*] in a compound heterozygous state, whereas two subjects have a splicing variant [c.23146-2A > G] in a homozygous state), 6 Friedreich ataxia (FA) patients and 12 healthy controls. Besides that, detailed clinical phenotyping and comprehensive neuropsychological assessment were carried out in all patients with ataxia. In addition to the characteristic cerebellar alterations, pyramidal signs and polyneuropathy were observed at least in 2 SYNE1 ataxia patients, for which no other underlying reason was found. The eye tracking assessment revealed hypometric saccades in the longer amplitude (18.4°) saccadic paradigm in all SYNE1 patients, whereas 2 out of 3 SYNE1 subjects performed slow saccades as well. In the antisaccade task, higher incorrect ratios of antisaccades were demonstrated in SYNE1 patients compared to healthy controls, showing inverse correlation with working memory test results. The corresponding data of FA patients was dispersed over a wide range, partially overlapping with control data. Conclusions The current study draws attention to the presence of eye movement disorders in patients with SYNE1 ataxia and demonstrates that alterations in the antisaccade paradigm may be related to working memory deficits.
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Affiliation(s)
- Laszlo Szpisjak
- Department of Neurology, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary
| | - Gabor Szaraz
- Department of Neurology, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary
| | - Andras Salamon
- Department of Neurology, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary
| | - Viola L Nemeth
- Department of Neurology, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary
| | - Noemi Szepfalusi
- Department of Neurology, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary
| | - Gabor Veres
- Department of Neurology, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.,MTA-SZTE Neuroscience Research Group, Szeged, Hungary
| | - Balint Kincses
- Department of Psychiatry, University of Szeged, Szeged, Hungary
| | - Zoltan Maroti
- Genetic Diagnostic Laboratory, Department of Pediatrics and Pediatric Health Center, University of Szeged, Szeged, Hungary
| | - Tibor Kalmar
- Genetic Diagnostic Laboratory, Department of Pediatrics and Pediatric Health Center, University of Szeged, Szeged, Hungary
| | | | - Rafal Ploski
- Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
| | - Peter Klivenyi
- Department of Neurology, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary
| | - Denes Zadori
- Department of Neurology, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary.
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44
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Kozono T, Sato H, Okumura W, Jogano C, Tamura-Nakano M, Kawamura YI, Rohrer J, Tonozuka T, Nishikawa A. The N-terminal region of Jaw1 has a role to inhibit the formation of organized smooth endoplasmic reticulum as an intrinsically disordered region. Sci Rep 2021; 11:753. [PMID: 33436890 PMCID: PMC7804115 DOI: 10.1038/s41598-020-80258-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Jaw1/LRMP is a type II integral membrane protein that is localized at the endoplasmic reticulum (ER) and outer nuclear membrane. We previously reported that a function of Jaw1 is to maintain the nuclear shape as a KASH protein via its carboxyl terminal region, a component of linker of nucleoskeleton and cytoskeleton complex in the oligomeric state. Although the oligomerization of some KASH proteins via the cytosolic regions serves to stabilize protein-protein interactions, the issue of how the oligomerization of Jaw1 is regulated is not completely understood. Therefore, we focused on three distinct regions on the cytosolic face of Jaw1: the N-terminal region, the coiled-coil domain and the stem region, in terms of oligomerization. A co-immunoprecipitation assay showed that its coiled-coil domain is a candidate for the oligomerization site. Furthermore, our data indicated that the N-terminal region prevents the aberrant oligomerization of Jaw1 as an intrinsically disordered region (IDR). Importantly, the ectopic expression of an N-terminal region deleted mutant caused the formation of organized smooth ER (OSER), structures such as nuclear karmellae and whorls, in B16F10 cells. Furthermore, this OSER interfered with the localization of the oligomer and interactors such as the type III inositol 1,4,5-triphosphate receptor (IP3R3) and SUN2. In summary, the N-terminal region of Jaw1 inhibits the formation of OSER as an IDR to maintain the homeostatic localization of interactors on the ER membrane.
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Affiliation(s)
- Takuma Kozono
- Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan.,Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, 272-8516, Japan
| | - Hiroyuki Sato
- Department of Applied Biological Chemistry, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan
| | - Wataru Okumura
- Department of Food and Energy Systems Science, Graduate School of Bio-Applications and Systems Engineering, Tokyo University of Agriculture and Technology, Tokyo, 184-8588, Japan
| | - Chifuyu Jogano
- Department of Applied Biological Chemistry, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan
| | - Miwa Tamura-Nakano
- Communal Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Yuki I Kawamura
- Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, 272-8516, Japan
| | - Jack Rohrer
- Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, CH-8820, Waedenswil, Switzerland
| | - Takashi Tonozuka
- Department of Applied Biological Chemistry, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan
| | - Atsushi Nishikawa
- Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan. .,Department of Applied Biological Chemistry, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan. .,Department of Food and Energy Systems Science, Graduate School of Bio-Applications and Systems Engineering, Tokyo University of Agriculture and Technology, Tokyo, 184-8588, Japan.
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45
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Genetic and Epidemiological Study of Adult Ataxia and Spastic Paraplegia in Eastern Quebec. Can J Neurol Sci 2021; 48:655-665. [PMID: 33397523 DOI: 10.1017/cjn.2020.277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To estimate the minimum prevalence of adult hereditary ataxias (HA) and spastic paraplegias (HSP) in Eastern Quebec and to evaluate the proportion of associated mutations in identified genes. METHODS We conducted a descriptive cross-sectional study of patients who met clinical criteria for the diagnosis of HA (n = 241) and HSP (n = 115) in the East of the Quebec province between January 2007 and July 2019. The primary outcome was the prevalence per 100,000 persons with a 95% confidence interval (CI). The secondary outcome was the frequency of mutations identified by targeted next-generation sequencing (NGS) approach. Minimum carrier frequency for identified variants was calculated based on allele frequency values and the Hardy-Weinberg (HW) equation. RESULTS The minimum prevalence of HA in Eastern Quebec was estimated at 6.47/100 000 [95% CI; 6.44-6.51]; divided into 3.73/100 000 for autosomal recessive (AR) ataxias and 2.67/100 000 for autosomal dominant (AD) ataxias. The minimum prevalence of HSP was 4.17/100 000 [95% CI; 4.14-4.2]; with 2.05/100 000 for AD-HSP and 2.12/100 000 for AR-HSP. In total, 52.4% of patients had a confirmed genetic diagnosis. AR cerebellar ataxia type 1 (2.67/100 000) and AD spastic paraplegia SPG4 (1.18/100 000) were the most prevalent disorders identified. Mutations were identified in 23 genes and molecular alterations in 7 trinucleotides repeats expansion; the most common mutations were c.15705-12 A > G in SYNE1 and c.1529C > T (p.A510V) in SPG7. CONCLUSIONS We described the minimum prevalence of genetically defined adult HA and HSP in Eastern Quebec. This study provides a framework for international comparisons and service planning.
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Delgado-Sequera A, Hidalgo-Figueroa M, Barrera-Conde M, Duran-Ruiz MC, Castro C, Fernández-Avilés C, de la Torre R, Sánchez-Gomar I, Pérez V, Geribaldi-Doldán N, Robledo P, Berrocoso E. Olfactory Neuroepithelium Cells from Cannabis Users Display Alterations to the Cytoskeleton and to Markers of Adhesion, Proliferation and Apoptosis. Mol Neurobiol 2020; 58:1695-1710. [PMID: 33237429 DOI: 10.1007/s12035-020-02205-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/09/2020] [Indexed: 12/26/2022]
Abstract
Cannabis is the third most commonly used psychoactive substance of abuse, yet it also receives considerable attention as a potential therapeutic drug. Therefore, it is essential to fully understand the actions of cannabis in the human brain. The olfactory neuroepithelium (ON) is a peripheral nervous tissue that represents an interesting surrogate model to study the effects of drugs in the brain, since it is closely related to the central nervous system, and sensory olfactory neurons are continually regenerated from populations of stem/progenitor cells that undergo neurogenesis throughout life. In this study, we used ON cells from chronic cannabis users and healthy control subjects to assess alterations in relevant cellular processes, and to identify changes in functional proteomic pathways due to cannabis consumption. The ON cells from cannabis users exhibited alterations in the expression of proteins that were related to the cytoskeleton, cell proliferation and cell death, as well as, changes in proteins implicated in cancer, gastrointestinal and neurodevelopmental pathologies. Subsequent studies showed cannabis provoked an increase in cell size and morphological alterations evident through β-Tubulin III staining, as well as, enhanced beta-actin expression and a decrease in the ability of ON cells to undergo cell attachment, suggesting abnormalities of the cytoskeleton and cell adhesion system. Furthermore, these cells proliferated more and underwent less cell death. Our results indicate that cannabis may alter key processes of the developing brain, some of which are similar to those reported in mental disorders like DiGeorge syndrome, schizophrenia and bipolar disorder.
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Affiliation(s)
- Alejandra Delgado-Sequera
- Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Campus Universitario Río San Pedro s/n, 11510, Puerto Real, Cadiz, Spain
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
| | - María Hidalgo-Figueroa
- Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Campus Universitario Río San Pedro s/n, 11510, Puerto Real, Cadiz, Spain
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Barrera-Conde
- Integrative Pharmacology and Systems Neuroscience, Neurosciences Research Programme, IMIM-Hospital del Mar Research Institute, PRBB, Calle Dr. Aiguader 88, 08003, Barcelona, Spain
- Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain
| | - Mª Carmen Duran-Ruiz
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
- Biomedicine, Biotechnology and Public Health Department, University of Cádiz, Cádiz, Spain
| | - Carmen Castro
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
- Biomedicine, Biotechnology and Public Health Department, University of Cádiz, Cádiz, Spain
| | | | - Rafael de la Torre
- Integrative Pharmacology and Systems Neuroscience, Neurosciences Research Programme, IMIM-Hospital del Mar Research Institute, PRBB, Calle Dr. Aiguader 88, 08003, Barcelona, Spain
- Biomedicine, Biotechnology and Public Health Department, University of Cádiz, Cádiz, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Ismael Sánchez-Gomar
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
- Biomedicine, Biotechnology and Public Health Department, University of Cádiz, Cádiz, Spain
| | - Víctor Pérez
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
- Neuropsychiatry and Addictions Institute (INAD) of Parc de Salut Mar, Barcelona, Spain
| | - Noelia Geribaldi-Doldán
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain
- Department of Human Anatomy and Embriology, University of Cádiz, Cádiz, Spain
| | - Patricia Robledo
- Integrative Pharmacology and Systems Neuroscience, Neurosciences Research Programme, IMIM-Hospital del Mar Research Institute, PRBB, Calle Dr. Aiguader 88, 08003, Barcelona, Spain.
- Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain.
| | - Esther Berrocoso
- Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Campus Universitario Río San Pedro s/n, 11510, Puerto Real, Cadiz, Spain.
- Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain.
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
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Titlow J, Robertson F, Järvelin A, Ish-Horowicz D, Smith C, Gratton E, Davis I. Syncrip/hnRNP Q is required for activity-induced Msp300/Nesprin-1 expression and new synapse formation. J Cell Biol 2020; 219:133707. [PMID: 32040548 PMCID: PMC7055005 DOI: 10.1083/jcb.201903135] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 08/21/2019] [Accepted: 12/12/2019] [Indexed: 01/09/2023] Open
Abstract
Memory and learning involve activity-driven expression of proteins and cytoskeletal reorganization at new synapses, requiring posttranscriptional regulation of localized mRNA a long distance from corresponding nuclei. A key factor expressed early in synapse formation is Msp300/Nesprin-1, which organizes actin filaments around the new synapse. How Msp300 expression is regulated during synaptic plasticity is poorly understood. Here, we show that activity-dependent accumulation of Msp300 in the postsynaptic compartment of the Drosophila larval neuromuscular junction is regulated by the conserved RNA binding protein Syncrip/hnRNP Q. Syncrip (Syp) binds to msp300 transcripts and is essential for plasticity. Single-molecule imaging shows that msp300 is associated with Syp in vivo and forms ribosome-rich granules that contain the translation factor eIF4E. Elevated neural activity alters the dynamics of Syp and the number of msp300:Syp:eIF4E RNP granules at the synapse, suggesting that these particles facilitate translation. These results introduce Syp as an important early acting activity-dependent regulator of a plasticity gene that is strongly associated with human ataxias.
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Affiliation(s)
- Joshua Titlow
- Department of Biochemistry, University of Oxford, Oxford, UK
| | | | - Aino Järvelin
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - David Ish-Horowicz
- Department of Biochemistry, University of Oxford, Oxford, UK.,Medical Research Council Lab for Molecular Cell Biology, University College London, London, UK
| | - Carlas Smith
- Centre for Neural Circuits and Behaviour, University of Oxford, Oxford, UK
| | - Enrico Gratton
- Laboratory for Fluorescence Dynamics, University of California Irvine, Irvine, CA
| | - Ilan Davis
- Department of Biochemistry, University of Oxford, Oxford, UK
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Autosomal Recessive Cerebellar Ataxia Type 1: Phenotypic and Genetic Correlation in a Cohort of Chinese Patients with SYNE1 Variants. THE CEREBELLUM 2020; 20:74-82. [PMID: 32889669 DOI: 10.1007/s12311-020-01186-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/27/2020] [Indexed: 10/23/2022]
Abstract
Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause autosomal recessive cerebellar ataxia (ARCA) type 1 with highly variable clinical phenotypes. The aim of this study was to describe the phenotypic-genetic spectrum of SYNE1-related ARCA1 patients in the Chinese population. We screened 158 unrelated patients with autosomal recessive or sporadic ataxia for variants in SYNE1 using next-generation sequencing. Pathogenicity assessment of SYNE1 variants was interpreted according to the American College of Medical Genetics standards and guidelines. We identified eight truncating variants and two missense variants spreading throughout the SYNE1 gene from six unrelated families, including nine novel variants and one reported variant. Of the six index patients, two patients showed the classical pure cerebellar ataxia, while four patients exhibited non-cerebellar phenotypes, including motor neuron symptoms, cognitive impairment, or mental retardation. The variants associated with motor neuron or cognition involvement tend to be located in the C-terminal region of SYNE1 protein, compared with the variants related to pure cerebellar ataxia. Our data indicating SYNE1 mutation is one of the more common causes of recessive ataxia in the Chinese population. The use of next-generation sequencing has enabled the rapid analysis of recessive ataxia and further expanded our understanding of genotype-phenotype correlation.
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Naruse H, Ishiura H, Mitsui J, Takahashi Y, Matsukawa T, Toda T, Tsuji S. Juvenile amyotrophic lateral sclerosis with complex phenotypes associated with novel SYNE1 mutations. Amyotroph Lateral Scler Frontotemporal Degener 2020; 22:576-578. [PMID: 32870032 DOI: 10.1080/21678421.2020.1813312] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mutations in SYNE1 have been originally described to cause a slowly progressive, pure cerebellar ataxia (spinocerebellar ataxia, autosomal-recessive 8; SCAR8). Notably, recent studies revealed that affected patients with SYNE1-associated ataxia can present with complex phenotypes rather than pure cerebellar ataxia, including motor neuron and brainstem dysfunctions. We herein report a Japanese patient diagnosed with juvenile amyotrophic lateral sclerosis (ALS) with a complex phenotype, who carried compound heterozygous pathogenic variants in SYNE1. Of the variants, one was a novel frameshift variant and the other was a nonsense variant previously reported as pathogenic for SCAR8. The patient showed an early age at onset with a relatively slow but progressive course of ALS, accompanied by cognitive decline. Our findings suggest that the clinical spectrum of patients carrying pathogenic SYNE1 variants is broader than expected, and SYNE1 variants should be considered in patients diagnosed with juvenile ALS, even without prominent cerebellar ataxia.
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Affiliation(s)
- Hiroya Naruse
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Ishiura
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jun Mitsui
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuji Takahashi
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan, and
| | - Takashi Matsukawa
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsushi Toda
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shoji Tsuji
- Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan
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Fallini C, Khalil B, Smith CL, Rossoll W. Traffic jam at the nuclear pore: All roads lead to nucleocytoplasmic transport defects in ALS/FTD. Neurobiol Dis 2020; 140:104835. [PMID: 32179176 DOI: 10.1016/j.nbd.2020.104835] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/25/2020] [Accepted: 03/12/2020] [Indexed: 02/06/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease that specifically affects the function and survival of spinal and cortical motor neurons. ALS shares many genetic, clinical, and pathological characteristics with frontotemporal dementia (FTD), and these diseases are now recognized as presentations of a disease spectrum known as ALS/FTD. The molecular determinants of neuronal loss in ALS/FTD are still debated, but the recent discovery of nucleocytoplasmic transport defects as a common denominator of most if not all forms of ALS/FTD has dramatically changed our understanding of the pathogenic mechanisms of this disease. Loss of nuclear pores and nucleoporin aggregation, altered nuclear morphology, and impaired nuclear transport are some of the most prominent features that have been identified using a variety of animal, cellular, and human models of disease. Here, we review the experimental evidence linking nucleocytoplasmic transport defects to the pathogenesis of ALS/FTD and propose a unifying view on how these defects may lead to a vicious cycle that eventually causes neuronal death.
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Affiliation(s)
- Claudia Fallini
- George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, USA; Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA; Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
| | - Bilal Khalil
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Courtney L Smith
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Wilfried Rossoll
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
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