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Ferrer RM, Jaspers YRJ, Dijkstra IME, Breeuwsma N, van Klinken J, Romero C, Engelen M, Kemp S, Heine VM. Altered lipid profile and reduced neuronal support in human induced pluripotent stem cell-derived astrocytes from adrenoleukodystrophy patients. J Inherit Metab Dis 2025; 48:e12832. [PMID: 39704488 PMCID: PMC11660744 DOI: 10.1002/jimd.12832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 12/03/2024] [Accepted: 12/03/2024] [Indexed: 12/21/2024]
Abstract
X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder resulting from pathogenic variants in the ABCD1 gene that primarily affects the nervous system and is characterized by progressive axonal degeneration in the spinal cord and peripheral nerves and leukodystrophy. Dysfunction of peroxisomal very long-chain fatty acid (VLCFA) degradation has been implicated in ALD pathology, but the impact on astrocytes, which critically support neuronal function, remains poorly understood. Fibroblasts from four ALD patients were reprogrammed to generate human-induced pluripotent stem cells (hiPSC). hiPSC-derived astrocytes were generated to study the impact of ALD on astrocytic fatty acid homeostasis. Our study reveals significant changes in the lipidome of ALD hiPSC-derived astrocytes, characterized by an enrichment of VLCFAs across multiple lipid classes, including triacylglycerols, cholesteryl esters, and phosphatidylcholines. Importantly, ALD hiPSC-derived astrocytes not only exhibit intrinsic lipid dysregulation but also affect the dendritic tree complexity of neurons in co-culture systems. These findings highlight the cell-autonomous effects of pathogenic variants in the ABCD1 protein on astrocytes and their microenvironment, shed light on potential mechanisms underlying ALD neuropathology, and underscore the critical role of astrocytes in neuronal health.
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Affiliation(s)
- Roberto Montoro Ferrer
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology MetabolismUniversity of AmsterdamAmsterdamThe Netherlands
- Department of Pediatric NeurologyEmma Children's Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, University of AmsterdamAmsterdamThe Netherlands
- Department of Complex Trait GeneticsCentre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit AmsterdamAmsterdamThe Netherlands
| | - Yorrick R. J. Jaspers
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology MetabolismUniversity of AmsterdamAmsterdamThe Netherlands
| | - Inge M. E. Dijkstra
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology MetabolismUniversity of AmsterdamAmsterdamThe Netherlands
| | - Nicole Breeuwsma
- Department of Child and Adolescence PsychiatryEmma Children's Hospital, Amsterdam UMC Location, Vrije Universiteit Amsterdam, Amsterdam NeuroscienceAmsterdamThe Netherlands
| | - Jan‐Bert van Klinken
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology MetabolismUniversity of AmsterdamAmsterdamThe Netherlands
- Core Facility MetabolomicsAmsterdam UMC Location, University of AmsterdamAmsterdamThe Netherlands
| | - Cato Romero
- Department of Complex Trait GeneticsCentre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit AmsterdamAmsterdamThe Netherlands
- Department of Child and Adolescence PsychiatryEmma Children's Hospital, Amsterdam UMC Location, Vrije Universiteit Amsterdam, Amsterdam NeuroscienceAmsterdamThe Netherlands
| | - Marc Engelen
- Department of Pediatric NeurologyEmma Children's Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, University of AmsterdamAmsterdamThe Netherlands
| | - Stephan Kemp
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology MetabolismUniversity of AmsterdamAmsterdamThe Netherlands
| | - Vivi M. Heine
- Department of Complex Trait GeneticsCentre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit AmsterdamAmsterdamThe Netherlands
- Department of Child and Adolescence PsychiatryEmma Children's Hospital, Amsterdam UMC Location, Vrije Universiteit Amsterdam, Amsterdam NeuroscienceAmsterdamThe Netherlands
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2
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Jaspers YRJ, Yska HAF, Bergner CG, Dijkstra IME, Huffnagel IC, Voermans MMC, Wever E, Salomons GS, Vaz FM, Jongejan A, Hermans J, Tryon RK, Lund TC, Köhler W, Engelen M, Kemp S. Lipidomic biomarkers in plasma correlate with disease severity in adrenoleukodystrophy. COMMUNICATIONS MEDICINE 2024; 4:175. [PMID: 39256476 PMCID: PMC11387402 DOI: 10.1038/s43856-024-00605-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 09/03/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder caused by pathogenic variants in ABCD1 resulting very long-chain fatty acids (VLCFA) accumulation in plasma and tissues. Males can present with various clinical manifestations, including adrenal insufficiency, spinal cord disease, and leukodystrophy. Female patients typically develop spinal cord disease and peripheral neuropathy. Predicting the clinical outcome of an individual patient remains impossible due to the lack of genotype-phenotype correlation and predictive biomarkers. METHODS The availability of a large prospective cohort of well-characterized patients and associated biobank samples allowed us to investigate the relationship between lipidome and disease severity in ALD. We performed a lipidomic analysis of plasma samples from 24 healthy controls, 92 male and 65 female ALD patients. RESULTS Here we show that VLCFA are incorporated into different lipid classes, including lysophosphatidylcholines, phosphatidylcholines, triglycerides, and sphingomyelins. Our results show a strong association between higher levels of VLCFA-containing lipids and the presence of leukodystrophy, adrenal insufficiency, and severe spinal cord disease in male ALD patients. In female ALD patients, VLCFA-lipid levels correlate with X-inactivation patterns in blood mononuclear cells, and higher levels are associated with more severe disease manifestations. Finally, hematopoietic stem cell transplantation significantly reduces, but does not normalize, plasma C26:0-lysophosphatidylcholine levels in male ALD patients. Our findings are supported by the concordance of C26:0-lysophosphatidylcholine and total VLCFA analysis with the lipidomics results. CONCLUSIONS This study reveals the profound impact of ALD on the lipidome and provides potential biomarkers for predicting clinical outcomes in ALD patients.
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Affiliation(s)
- Yorrick R J Jaspers
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Hemmo A F Yska
- Department of Pediatric Neurology, Amsterdam UMC location University of Amsterdam, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Caroline G Bergner
- Department of Neurology, Leukodystrophy Outpatient Clinic, Leipzig University Medical Center, Leipzig, Germany
| | - Inge M E Dijkstra
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Irene C Huffnagel
- Department of Pediatric Neurology, Amsterdam UMC location University of Amsterdam, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Marije M C Voermans
- Department of Pediatric Neurology, Amsterdam UMC location University of Amsterdam, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Eric Wever
- Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Gajja S Salomons
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- Department of Pediatrics, Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands
| | - Frédéric M Vaz
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Aldo Jongejan
- Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Jill Hermans
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Rebecca K Tryon
- Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Children's Hospital, Minneapolis, MN, USA
| | - Troy C Lund
- Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Children's Hospital, Minneapolis, MN, USA
| | - Wolfgang Köhler
- Department of Neurology, Leukodystrophy Outpatient Clinic, Leipzig University Medical Center, Leipzig, Germany
| | - Marc Engelen
- Department of Pediatric Neurology, Amsterdam UMC location University of Amsterdam, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Stephan Kemp
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
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3
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Jaspers YRJ, Meyer SW, Pras-Raves ML, Dijkstra IME, Wever EJM, Dane AD, van Klinken JB, Salomons GS, Houtkooper RH, Engelen M, Kemp S, Van Weeghel M, Vaz FM. Four-dimensional lipidomics profiling in X-linked adrenoleukodystrophy using trapped ion mobility mass spectrometry. J Lipid Res 2024; 65:100567. [PMID: 38795862 PMCID: PMC11234049 DOI: 10.1016/j.jlr.2024.100567] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 05/15/2024] [Accepted: 05/16/2024] [Indexed: 05/28/2024] Open
Abstract
Lipids play pivotal roles in an extensive range of metabolic and physiological processes. In recent years, the convergence of trapped ion mobility spectrometry and MS has enabled 4D-lipidomics, a highly promising technology for comprehensive lipid analysis. 4D-lipidomics assesses lipid annotations across four distinct dimensions-retention time, collisional cross section, m/z (mass-to-charge ratio), and MS/MS spectra-providing a heightened level of confidence in lipid annotation. These advantages prove particularly valuable when investigating complex disorders involving lipid metabolism, such as adrenoleukodystrophy (ALD). ALD is characterized by the accumulation of very-long-chain fatty acids (VLCFAs) due to pathogenic variants in the ABCD1 gene. A comprehensive 4D-lipidomics strategy of ALD fibroblasts demonstrated significant elevations of various lipids from multiple classes. This indicates that the changes observed in ALD are not confined to a single lipid class and likely impacts a broad spectrum of lipid-mediated physiological processes. Our findings highlight the incorporation of mainly saturated and monounsaturated VLCFA variants into a range of lipid classes, encompassing phosphatidylcholines, triacylglycerols, and cholesterol esters. These include ultra-long-chain fatty acids with a length of up to thirty carbon atoms. Lipid species containing C26:0 and C26:1 were the most frequently detected VLCFA lipids in our study. Furthermore, we report a panel of 121 new candidate biomarkers in fibroblasts, exhibiting significant differentiation between controls and individuals with ALD. In summary, this study demonstrates the capabilities of a 4D-lipid profiling workflow in unraveling novel insights into the intricate lipid modifications associated with metabolic disorders like ALD.
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Affiliation(s)
- Yorrick R J Jaspers
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism Institute, Amsterdam, The Netherlands; Amsterdam Neuroscience institute, Amsterdam, The Netherlands
| | | | - Mia L Pras-Raves
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Inge M E Dijkstra
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Eric J M Wever
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Adrie D Dane
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Jan-Bert van Klinken
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Gajja S Salomons
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Riekelt H Houtkooper
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism Institute, Amsterdam, The Netherlands; Emma Center for Personalized Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Marc Engelen
- Amsterdam Neuroscience institute, Amsterdam, The Netherlands; Department of Pediatric Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Stephan Kemp
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism Institute, Amsterdam, The Netherlands; Amsterdam Neuroscience institute, Amsterdam, The Netherlands.
| | - Michel Van Weeghel
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism Institute, Amsterdam, The Netherlands; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Frédéric M Vaz
- Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism Institute, Amsterdam, The Netherlands; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
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Role of Omega-Hydroxy Ceramides in Epidermis: Biosynthesis, Barrier Integrity and Analyzing Method. Int J Mol Sci 2023; 24:ijms24055035. [PMID: 36902463 PMCID: PMC10003399 DOI: 10.3390/ijms24055035] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/19/2023] [Accepted: 02/25/2023] [Indexed: 03/08/2023] Open
Abstract
Attached to the outer surface of the corneocyte lipid envelope (CLE), omega-hydroxy ceramides (ω-OH-Cer) link to involucrin and function as lipid components of the stratum corneum (SC). The integrity of the skin barrier is highly dependent on the lipid components of SC, especially on ω-OH-Cer. Synthetic ω-OH-Cer supplementation has been utilized in clinical practice for epidermal barrier injury and related surgeries. However, the mechanism discussion and analyzing methods are not keeping pace with its clinical application. Though mass spectrometry (MS) is the primary choice for biomolecular analysis, method modifications for ω-OH-Cer identification are lacking in progress. Therefore, finding conclusions on ω-OH-Cer biological function, as well as on its identification, means it is vital to remind further researchers of how the following work should be done. This review summarizes the important role of ω-OH-Cer in epidermal barrier functions and the forming mechanism of ω-OH-Cer. Recent identification methods for ω-OH-Cer are also discussed, which could provide new inspirations for study on both ω-OH-Cer and skin care development.
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5
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Gupta AO, Raymond G, Pierpont RI, Kemp S, McIvor RS, Rayannavar A, Miller B, Lund TC, Orchard PJ. Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy. Expert Opin Biol Ther 2022; 22:1151-1162. [DOI: 10.1080/14712598.2022.2124857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Ashish O Gupta
- Division of Pediatric Blood and Marrow Transplant and Cellular Therapies, University of Minnesota
| | - Gerald Raymond
- Division of Neurogenetics and The Moser Center for Leukodystrophies, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland, USA
| | - Rene I Pierpont
- Division of Clinical Behavioral Neuroscience, Department of Pediatrics, University of Minnesota
| | - Stephan Kemp
- Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC - University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Neuroscience, 1105 AZ Amsterdam, The Netherlands
| | - R Scott McIvor
- Department of Genetics, Cell Biology and Development, Center for Genome Engineering, University of Minnesota
| | | | - Bradley Miller
- Division of Pediatric Endocrinology, University of Minnesota
| | - Troy C Lund
- Division of Pediatric Blood and Marrow Transplant and Cellular Therapies, University of Minnesota
| | - Paul J Orchard
- Division of Pediatric Blood and Marrow Transplant and Cellular Therapies, University of Minnesota
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Li H, Herrmann T, Seeßle J, Liebisch G, Merle U, Stremmel W, Chamulitrat W. Role of fatty acid transport protein 4 in metabolic tissues: insights into obesity and fatty liver disease. Biosci Rep 2022; 42:BSR20211854. [PMID: 35583196 PMCID: PMC9160530 DOI: 10.1042/bsr20211854] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 11/28/2022] Open
Abstract
Fatty acid (FA) metabolism is a series of processes that provide structural substances, signalling molecules and energy. Ample evidence has shown that FA uptake is mediated by plasma membrane transporters including FA transport proteins (FATPs), caveolin-1, fatty-acid translocase (FAT)/CD36, and fatty-acid binding proteins. Unlike other FA transporters, the functions of FATPs have been controversial because they contain both motifs of FA transport and fatty acyl-CoA synthetase (ACS). The widely distributed FATP4 is not a direct FA transporter but plays a predominant function as an ACS. FATP4 deficiency causes ichthyosis premature syndrome in mice and humans associated with suppression of polar lipids but an increase in neutral lipids including triglycerides (TGs). Such a shift has been extensively characterized in enterocyte-, hepatocyte-, and adipocyte-specific Fatp4-deficient mice. The mutants under obese and non-obese fatty livers induced by different diets persistently show an increase in blood non-esterified free fatty acids and glycerol indicating the lipolysis of TGs. This review also focuses on FATP4 role on regulatory networks and factors that modulate FATP4 expression in metabolic tissues including intestine, liver, muscle, and adipose tissues. Metabolic disorders especially regarding blood lipids by FATP4 deficiency in different cell types are herein discussed. Our results may be applicable to not only patients with FATP4 mutations but also represent a model of dysregulated lipid homeostasis, thus providing mechanistic insights into obesity and development of fatty liver disease.
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Affiliation(s)
- Huili Li
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Thomas Herrmann
- Westkuesten Hospital, Esmarchstraße 50, 25746 Heide, Germany
| | - Jessica Seeßle
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
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Terluk MR, Tieu J, Sahasrabudhe SA, Moser A, Watkins PA, Raymond GV, Kartha RV. Nervonic Acid Attenuates Accumulation of Very Long-Chain Fatty Acids and is a Potential Therapy for Adrenoleukodystrophy. Neurotherapeutics 2022; 19:1007-1017. [PMID: 35378685 PMCID: PMC9294126 DOI: 10.1007/s13311-022-01226-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2022] [Indexed: 12/23/2022] Open
Abstract
Adrenoleukodystrophy (ALD) is an X-linked inherited peroxisomal disorder due to mutations in the ALD protein and characterized by accumulation of very long-chain fatty acids (VLCFA), specifically hexacosanoic acid (C26:0). This can trigger other pathological processes such as mitochondrial dysfunction, oxidative stress, and inflammation, which if involves the brain tissues can result in a lethal form of the disease called childhood cerebral ALD. With the recent addition of ALD to the Recommended Uniform Screening Panel, there is an increase in the number of individuals who are identified with ALD. However, currently, there is no approved treatment for pre-symptomatic individuals that can arrest or delay symptom development. Here, we report our observations investigating nervonic acid, a monounsaturated fatty acid as a potential therapy for ALD. Using ALD patient-derived fibroblasts, we examined whether nervonic acid can reverse VLCFA accumulation similar to erucic acid, the active ingredient in Lorenzo's oil, a dietary intervention believed to alter disease course. We have shown that nervonic acid can reverse total lipid C26:0 accumulation in a concentration-dependent manner in ALD cell lines. Further, we show that nervonic acid can protect ALD fibroblasts from oxidative insults, presumably by increasing intracellular ATP production. Thus, nervonic acid can be a potential therapeutic for individuals with ALD, which can alter cellular biochemistry and improve its function.
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Affiliation(s)
- Marcia R Terluk
- Center for Orphan Drug Research, University of Minnesota, McGuire Translational Research Facility, 2001 6th St SE, Minneapolis, MN, 55455, USA
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Julianne Tieu
- Center for Orphan Drug Research, University of Minnesota, McGuire Translational Research Facility, 2001 6th St SE, Minneapolis, MN, 55455, USA
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Siddhee A Sahasrabudhe
- Center for Orphan Drug Research, University of Minnesota, McGuire Translational Research Facility, 2001 6th St SE, Minneapolis, MN, 55455, USA
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Ann Moser
- Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, 21205, USA
- Department of Neurology, John Hopkins University, Baltimore, MD, 21287, USA
| | - Paul A Watkins
- Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, 21205, USA
- Department of Neurology, John Hopkins University, Baltimore, MD, 21287, USA
| | - Gerald V Raymond
- Department of Neurology, John Hopkins University, Baltimore, MD, 21287, USA
- Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Reena V Kartha
- Center for Orphan Drug Research, University of Minnesota, McGuire Translational Research Facility, 2001 6th St SE, Minneapolis, MN, 55455, USA.
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.
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Zarekiani P, Breur M, Wolf NI, de Vries HE, van der Knaap MS, Bugiani M. Pathology of the neurovascular unit in leukodystrophies. Acta Neuropathol Commun 2021; 9:103. [PMID: 34082828 PMCID: PMC8173888 DOI: 10.1186/s40478-021-01206-6] [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: 04/13/2021] [Accepted: 05/24/2021] [Indexed: 01/20/2023] Open
Abstract
The blood-brain barrier is a dynamic endothelial cell barrier in the brain microvasculature that separates the blood from the brain parenchyma. Specialized brain endothelial cells, astrocytes, neurons, microglia and pericytes together compose the neurovascular unit and interact to maintain blood-brain barrier function. A disturbed brain barrier function is reported in most common neurological disorders and may play a role in disease pathogenesis. However, a comprehensive overview of how the neurovascular unit is affected in a wide range of rare disorders is lacking. Our aim was to provide further insights into the neuropathology of the neurovascular unit in leukodystrophies to unravel its potential pathogenic role in these diseases. Leukodystrophies are monogenic disorders of the white matter due to defects in any of its structural components. Single leukodystrophies are exceedingly rare, and availability of human tissue is unique. Expression of selective neurovascular unit markers such as claudin-5, zona occludens 1, laminin, PDGFRβ, aquaporin-4 and α-dystroglycan was investigated in eight different leukodystrophies using immunohistochemistry. We observed tight junction rearrangements, indicative of endothelial dysfunction, in five out of eight assessed leukodystrophies of different origin and an altered aquaporin-4 distribution in all. Aquaporin-4 redistribution indicates a general astrocytic dysfunction in leukodystrophies, even in those not directly related to astrocytic pathology or without prominent reactive astrogliosis. These findings provide further evidence for dysfunction in the orchestration of the neurovascular unit in leukodystrophies and contribute to a better understanding of the underlying disease mechanism.
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Affiliation(s)
- Parand Zarekiani
- Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, de Boelelaan 1117, 1081HV Amsterdam, The Netherlands
- Amsterdam Leukodystrophy Center, Amsterdam UMC, Amsterdam, The Netherlands
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Marjolein Breur
- Amsterdam Leukodystrophy Center, Amsterdam UMC, Amsterdam, The Netherlands
- Department of Child Neurology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Nicole I. Wolf
- Amsterdam Leukodystrophy Center, Amsterdam UMC, Amsterdam, The Netherlands
- Department of Child Neurology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Helga E. de Vries
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Marjo S. van der Knaap
- Amsterdam Leukodystrophy Center, Amsterdam UMC, Amsterdam, The Netherlands
- Department of Child Neurology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Marianna Bugiani
- Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, de Boelelaan 1117, 1081HV Amsterdam, The Netherlands
- Amsterdam Leukodystrophy Center, Amsterdam UMC, Amsterdam, The Netherlands
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9
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Montoro R, Heine VM, Kemp S, Engelen M. Evolution of adrenoleukodystrophy model systems. J Inherit Metab Dis 2021; 44:544-553. [PMID: 33373044 PMCID: PMC8248356 DOI: 10.1002/jimd.12357] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/23/2020] [Accepted: 12/28/2020] [Indexed: 01/09/2023]
Abstract
X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder affecting the adrenal glands, testes, spinal cord and brain. The disease is caused by mutations in the ABCD1 gene resulting in a defect in peroxisomal degradation of very long-chain fatty acids and their accumulation in plasma and tissues. Males with ALD have a near 100% life-time risk to develop myelopathy. The life-time prevalence to develop progressive cerebral white matter lesions (known as cerebral ALD) is about 60%. Adrenal insufficiency occurs in about 80% of male patients. In adulthood, 80% of women with ALD also develop myelopathy, but adrenal insufficiency or cerebral ALD are very rare. The complex clinical presentation and the absence of a genotype-phenotype correlation are complicating our understanding of the disease. In an attempt to understand the pathophysiology of ALD various model systems have been developed. While these model systems share the basic genetics and biochemistry of ALD they fail to fully recapitulate the complex neurodegenerative etiology of ALD. Each model system recapitulates certain aspects of the disorder. This exposes the complexity of ALD and therefore the challenge to create a comprehensive model system to fully understand ALD. In this review, we provide an overview of the different ALD modeling strategies from single-celled to multicellular organisms and from in vitro to in vivo approaches, and introduce how emerging iPSC-derived technologies could improve the understanding of this highly complex disorder.
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Affiliation(s)
- Roberto Montoro
- Department of Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, Amsterdam NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
| | - Vivi M. Heine
- Department of Child and Youth Psychiatry, Amsterdam UMC, Amsterdam NeuroscienceVrije Universiteit AmsterdamAmsterdamThe Netherlands
- Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, Amsterdam NeuroscienceVrije Universiteit AmsterdamAmsterdamThe Netherlands
| | - Stephan Kemp
- Department of Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, Amsterdam NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
- Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, Amsterdam Gastroenterology & MetabolismUniversity of AmsterdamAmsterdamThe Netherlands
| | - Marc Engelen
- Department of Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, Amsterdam NeuroscienceUniversity of AmsterdamAmsterdamThe Netherlands
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Raas Q, van de Beek MC, Forss-Petter S, Dijkstra IM, Deschiffart A, Freshner BC, Stevenson TJ, Jaspers YR, Nagtzaam L, Wanders RJ, van Weeghel M, Engelen-Lee JY, Engelen M, Eichler F, Berger J, Bonkowsky JL, Kemp S. Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy. J Clin Invest 2021; 131:142500. [PMID: 33690217 DOI: 10.1172/jci142500] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 03/03/2021] [Indexed: 12/18/2022] Open
Abstract
X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease caused by mutations in ABCD1, the peroxisomal very long-chain fatty acid (VLCFA) transporter. ABCD1 deficiency results in accumulation of saturated VLCFAs. A drug screen using a phenotypic motor assay in a zebrafish ALD model identified chloroquine as the top hit. Chloroquine increased expression of stearoyl-CoA desaturase-1 (scd1), the enzyme mediating fatty acid saturation status, suggesting that a shift toward monounsaturated fatty acids relieved toxicity. In human ALD fibroblasts, chloroquine also increased SCD1 levels and reduced saturated VLCFAs. Conversely, pharmacological inhibition of SCD1 expression led to an increase in saturated VLCFAs, and CRISPR knockout of scd1 in zebrafish mimicked the motor phenotype of ALD zebrafish. Importantly, saturated VLCFAs caused ER stress in ALD fibroblasts, whereas monounsaturated VLCFA did not. In parallel, we used liver X receptor (LXR) agonists to increase SCD1 expression, causing a shift from saturated toward monounsaturated VLCFA and normalizing phospholipid profiles. Finally, Abcd1-/y mice receiving LXR agonist in their diet had VLCFA reductions in ALD-relevant tissues. These results suggest that metabolic rerouting of saturated to monounsaturated VLCFAs may alleviate lipid toxicity, a strategy that may be beneficial in ALD and other peroxisomal diseases in which VLCFAs play a key role.
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Affiliation(s)
- Quentin Raas
- Department of Pediatrics, University of Utah, Brain and Spine Center, Primary Children's Hospital, Salt Lake City, Utah, USA
| | - Malu-Clair van de Beek
- Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, Amsterdam Gastroenterology & Metabolism, University of Amsterdam, Amsterdam, Netherlands
| | - Sonja Forss-Petter
- Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Inge Me Dijkstra
- Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, Amsterdam Gastroenterology & Metabolism, University of Amsterdam, Amsterdam, Netherlands
| | - Abigail Deschiffart
- Department of Pediatrics, University of Utah, Brain and Spine Center, Primary Children's Hospital, Salt Lake City, Utah, USA
| | - Briana C Freshner
- Department of Pediatrics, University of Utah, Brain and Spine Center, Primary Children's Hospital, Salt Lake City, Utah, USA
| | - Tamara J Stevenson
- Department of Pediatrics, University of Utah, Brain and Spine Center, Primary Children's Hospital, Salt Lake City, Utah, USA
| | - Yorrick Rj Jaspers
- Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, Amsterdam Gastroenterology & Metabolism, University of Amsterdam, Amsterdam, Netherlands
| | - Liselotte Nagtzaam
- Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, Amsterdam Gastroenterology & Metabolism, University of Amsterdam, Amsterdam, Netherlands
| | - Ronald Ja Wanders
- Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, Amsterdam Gastroenterology & Metabolism, University of Amsterdam, Amsterdam, Netherlands
| | - Michel van Weeghel
- Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, Amsterdam Gastroenterology & Metabolism, University of Amsterdam, Amsterdam, Netherlands
| | - Joo-Yeon Engelen-Lee
- Department of Neurology, Amsterdam UMC, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, Netherlands
| | - Marc Engelen
- Department of Pediatric Neurology, Amsterdam UMC, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, Netherlands
| | - Florian Eichler
- Massachusetts General Hospital, Harvard Medical School, Boston, USA
| | - Johannes Berger
- Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Joshua L Bonkowsky
- Department of Pediatrics, University of Utah, Brain and Spine Center, Primary Children's Hospital, Salt Lake City, Utah, USA
| | - Stephan Kemp
- Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, Amsterdam Gastroenterology & Metabolism, University of Amsterdam, Amsterdam, Netherlands.,Department of Pediatric Neurology, Amsterdam UMC, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, Netherlands
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11
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Yazd HS, Rubio VY, Chamberlain CA, Yost RA, Garrett TJ. Metabolomic and lipidomic characterization of an X-chromosome deletion disorder in neural progenitor cells by UHPLC-HRMS. J Mass Spectrom Adv Clin Lab 2021; 20:11-24. [PMID: 34820667 PMCID: PMC8601009 DOI: 10.1016/j.jmsacl.2021.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 05/05/2021] [Accepted: 05/24/2021] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Intellectual disorders involving deletions of the X chromosome present a difficult task in the determination of a connection between symptoms and metabolites that could lead to treatment options. One specific disorder of X-chromosomal deletion, Fragile X syndrome, is the most frequently occurring of intellectual disabilities. Previous metabolomic studies have been limited to mouse models that may not have sufficiently revealed the full biochemical diversity of the disease in humans. OBJECTIVES The primary objective of this study was to elucidate the human biochemistry in X-chromosomal deletion disorders through metabolomic and lipidomic profiling, using cells from a X-deletion patient as a representative case. METHODS Metabolomic and lipidomic analysis was performed by UHPLC-HRMS on neural progenitor (NP) cells isolated from an afflicted female patient versus normal neural progenitor cells. RESULTS Results showed perturbations in several metabolic pathways, including those of arginine and proline, that significantly impact both neurotransmitter generation and overall brain function. Coincidently, dysregulation was observed for lipids involved in both cellular structure and membrane integrity. The trends of observed metabolomic changes, as well as lipidomic profiling from identified features, are discussed. CONCLUSION The lipidomic and metabolomic profiles of NP cell samples exhibited significant differentiation associated with partial deletion of the X chromosome. These findings suggest that rare X-chromosomal deletion disorders are not only a mental disorder limited to alterations in local neuronal functions, but are also metabolic diseases.
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Key Words
- BMP, Bis(monoacylglycero) phosphate
- Cer-NS, Ceramide nonhydroxyfatty acid-sphingosines
- Fragile X syndrome
- GL, Glycerolipid
- HexCer-NS, Hexosylceramide nonhydroxyfatty acid-sphingosines
- LPC, Lysophosphatidylcholines
- Lipidomics
- Metabolomics
- Microdeletion
- PC, Phosphatidylcholine
- PE, Phosphatidylethanolamine
- PG, Phosphatidylglycerol
- SM, Sphingomyelin
- SP, Sphingolipid
- ST, Sterol
- Xq27.3-Xq28
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Affiliation(s)
- Hoda Safari Yazd
- Department of Chemistry, University of Florida, Gainesville, FL 32610, USA
| | - Vanessa Y. Rubio
- Department of Chemistry, University of Florida, Gainesville, FL 32610, USA
- Department of Chemistry & Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27412, USA
| | - Casey A. Chamberlain
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
- Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Richard A. Yost
- Department of Chemistry, University of Florida, Gainesville, FL 32610, USA
| | - Timothy J. Garrett
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
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Abstract
X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and characterized by impaired very long-chain fatty acid beta-oxidation. Clinically, male patients develop adrenal failure and a progressive myelopathy in adulthood, although age of onset and rate of progression are highly variable. Additionally, 40% of male patients develop a leukodystrophy (cerebral ALD) before the age of 18 years. Women with ALD also develop a myelopathy but generally at a later age than men and with slower progression. Adrenal failure and leukodystrophy are exceedingly rare in women. Allogeneic hematopoietic cell transplantation (HCT), or more recently autologous HCT with ex vivo lentivirally transfected bone marrow, halts the leukodystrophy. Unfortunately, there is no curative treatment for the myelopathy. In the following chapter, the biochemistry, pathology, and clinical spectrum of ALD are discussed in detail.
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Affiliation(s)
- Marc Engelen
- Department of Pediatric Neurology, Emma Children's Hospital, and Amsterdam Leukodystrophy Center, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
| | - Stephan Kemp
- Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Florian Eichler
- Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
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13
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Palakuzhiyil SV, Christopher R, Chandra SR. Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy. World J Biol Chem 2020; 11:99-111. [PMID: 33274015 PMCID: PMC7672940 DOI: 10.4331/wjbc.v11.i3.99] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/10/2020] [Accepted: 09/18/2020] [Indexed: 02/05/2023] Open
Abstract
X-linked adrenoleukodystrophy (X-ALD), an inborn error of peroxisomal β-oxidation, is caused by defects in the ATP Binding Cassette Subfamily D Member 1 (ABCD1) gene. X-ALD patients may be asymptomatic or present with several clinical phenotypes varying from severe to mild, severe cerebral adrenoleuko-dystrophy to mild adrenomyeloneuropathy (AMN). Although most female heterozygotes present with AMN-like symptoms after 60 years of age, occasional cases of females with the cerebral form have been reported. Phenotypic variability has been described within the same kindreds and even among monozygotic twins. There is no association between the nature of ABCD1 mutation and the clinical phenotypes, and the molecular basis of phenotypic variability in X-ALD is yet to be resolved. Various genetic, epigenetic, and environmental influences are speculated to modify the disease onset and severity. In this review, we summarize the observations made in various studies investigating the potential modifying factors regulating the clinical manifestation of X-ALD, which could help understand the pathogenesis of the disease and develop suitable therapeutic strategies.
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Affiliation(s)
- Shruti V Palakuzhiyil
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bengaluru 560029, India
| | - Rita Christopher
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bengaluru 560029, India
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Cerebellar and hepatic alterations in ACBD5-deficient mice are associated with unexpected, distinct alterations in cellular lipid homeostasis. Commun Biol 2020; 3:713. [PMID: 33244184 PMCID: PMC7691522 DOI: 10.1038/s42003-020-01442-x] [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: 03/04/2020] [Accepted: 10/31/2020] [Indexed: 11/27/2022] Open
Abstract
ACBD5 deficiency is a novel peroxisome disorder with a largely uncharacterized pathology. ACBD5 was recently identified in a tethering complex mediating membrane contacts between peroxisomes and the endoplasmic reticulum (ER). An ACBD5-deficient mouse was analyzed to correlate ACBD5 tethering functions with the disease phenotype. ACBD5-deficient mice exhibit elevated very long-chain fatty acid levels and a progressive cerebellar pathology. Liver did not exhibit pathologic changes but increased peroxisome abundance and drastically reduced peroxisome-ER contacts. Lipidomics of liver and cerebellum revealed tissue-specific alterations in distinct lipid classes and subspecies. In line with the neurological pathology, unusual ultra-long chain fatty acids (C > 32) were elevated in phosphocholines from cerebelli but not liver indicating an organ-specific imbalance in fatty acid degradation and elongation pathways. By contrast, ether lipid formation was perturbed in liver towards an accumulation of alkyldiacylglycerols. The alterations in several lipid classes suggest that ACBD5, in addition to its acyl-CoA binding function, might maintain peroxisome-ER contacts in order to contribute to the regulation of anabolic and catabolic cellular lipid pathways. Darwisch, von Spangenberg et al. show that ACBD5‐deficient mice exhibit elevated levels of very long‐chain fatty acids and a progressive cerebellar pathology. A complex metabolic phenotype suggests that ACBD5 with its acyl‐CoA binding and peroxisome‐ER tethering functions might contribute to the regulation of anabolic and catabolic cellular lipid pathways.
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15
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Erdbrügger P, Fröhlich F. The role of very long chain fatty acids in yeast physiology and human diseases. Biol Chem 2020; 402:25-38. [PMID: 33544487 DOI: 10.1515/hsz-2020-0234] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 11/02/2020] [Indexed: 12/16/2022]
Abstract
Fatty acids (FAs) are a highly diverse class of molecules that can have variable chain length, number of double bonds and hydroxylation sites. FAs with 22 or more carbon atoms are described as very long chain fatty acids (VLCFAs). VLCFAs are synthesized in the endoplasmic reticulum (ER) through a four-step elongation cycle by membrane embedded enzymes. VLCFAs are precursors for the synthesis of sphingolipids (SLs) and glycerophospholipids. Besides their role as lipid constituents, VLCFAs are also found as precursors of lipid mediators. Mis-regulation of VLCFA metabolism can result in a variety of inherited diseases ranging from ichthyosis, to myopathies and demyelination. The enzymes for VLCFA biosynthesis are evolutionary conserved and many of the pioneering studies were performed in the model organism Saccharomyces cerevisiae. A growing body of evidence suggests that VLCFA metabolism is intricately regulated to maintain lipid homeostasis. In this review we will describe the metabolism of VLCFAs, how they are synthesized, transported and degraded and how these processes are regulated, focusing on budding yeast. We will review how lipid metabolism and membrane properties are affected by VLCFAs and which impact mutations in the biosynthetic genes have on physiology. We will also briefly describe diseases caused by mis-regulation of VLCFAs in human cells.
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Affiliation(s)
- Pia Erdbrügger
- Department of Biology/Chemistry, Molecular Membrane Biology Group, University of Osnabrück, Osnabrück, Germany
| | - Florian Fröhlich
- Department of Biology/Chemistry, Molecular Membrane Biology Group, University of Osnabrück, Osnabrück, Germany.,Center of Cellular Nanoanalytics Osnabrück, Osnabrück, Germany
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16
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Islinger M, Costello JL, Kors S, Soupene E, Levine TP, Kuypers FA, Schrader M. The diversity of ACBD proteins - From lipid binding to protein modulators and organelle tethers. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2020; 1867:118675. [PMID: 32044385 PMCID: PMC7057175 DOI: 10.1016/j.bbamcr.2020.118675] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 01/30/2020] [Accepted: 02/05/2020] [Indexed: 12/12/2022]
Abstract
Members of the large multigene family of acyl-CoA binding domain containing proteins (ACBDs) share a conserved motif required for binding of Coenzyme A esterified fatty acids of various chain length. These proteins are present in the three kingdoms of life, and despite their predicted roles in cellular lipid metabolism, knowledge about the precise functions of many ACBD proteins remains scarce. Interestingly, several ACBD proteins are now suggested to function at organelle contact sites, and are recognized as host interaction proteins for different pathogens including viruses and bacteria. Here, we present a thorough phylogenetic analysis of the ACBD family and discuss their structure and evolution. We summarize recent findings on the various functions of animal and fungal ACBDs with particular focus on peroxisomes, the role of ACBD proteins at organelle membranes, and their increasing recognition as targets for pathogens.
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Affiliation(s)
- Markus Islinger
- Institute of Neuroanatomy, Medical Faculty Manheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Joseph L Costello
- College of Life and Environmental Sciences, Biosciences, University of Exeter, Exeter EX4 4QD, Devon, UK
| | - Suzan Kors
- College of Life and Environmental Sciences, Biosciences, University of Exeter, Exeter EX4 4QD, Devon, UK
| | - Eric Soupene
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
| | | | - Frans A Kuypers
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
| | - Michael Schrader
- College of Life and Environmental Sciences, Biosciences, University of Exeter, Exeter EX4 4QD, Devon, UK.
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Lee DK, Long NP, Jung J, Kim TJ, Na E, Kang YP, Kwon SW, Jang J. Integrative lipidomic and transcriptomic analysis of X-linked adrenoleukodystrophy reveals distinct lipidome signatures between adrenomyeloneuropathy and childhood cerebral adrenoleukodystrophy. Biochem Biophys Res Commun 2018; 508:563-569. [PMID: 30509496 DOI: 10.1016/j.bbrc.2018.11.123] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 11/20/2018] [Indexed: 12/16/2022]
Abstract
Precise pathophysiology with respect to the phenotypic variations and severity of X-ALD, specifically between adrenomyeloneuropathy (AMN) and childhood cerebral adrenoleukodystrophy (CCALD), has not been fully discovered. Herein, a systematic analysis using multi-layered lipidomics and transcriptomics was conducted to elucidate distinctive metabolic biosignatures among healthy control, AMN, and CCALD. Significant alterations regarding the accumulation of very long chain fatty acids were found in various lipid species such as phospholipids, glycerolipids, and sphingolipids. Remarkably, TG and CER that are physiologically essential were markedly down-regulated in CCALD than AMN. Transcriptomic analysis further supported the robustness of our findings by providing valuable information on the gene expressions of the regulatory factors. For instance, regulators of sphingolipid catabolism (SMPD1, CERK, and SPHK1) and TG anabolism (GPAM, GPAT2, and MBOAT2) were more up-regulated in AMN than in CCALD. These observations, among others, were in line with the recognized alterations of the associated lipidomes. In conclusion, the homeostatic imbalance of the complex lipid networks may be pathogenically important in X-ALD and the particular dysregulations of TG and CER may further influence the severity of CCALD among X-ALD patients.
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Affiliation(s)
- Dong-Kyu Lee
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Nguyen Phuoc Long
- College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Juwon Jung
- Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul, 03080, Republic of Korea
| | - Tae Joon Kim
- College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Euiyeon Na
- College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yun Pyo Kang
- College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Sung Won Kwon
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea; College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
| | - Jiho Jang
- Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
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18
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Lipid-induced endoplasmic reticulum stress in X-linked adrenoleukodystrophy. Biochim Biophys Acta Mol Basis Dis 2017; 1863:2255-2265. [PMID: 28666219 DOI: 10.1016/j.bbadis.2017.06.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 05/16/2017] [Accepted: 06/01/2017] [Indexed: 12/20/2022]
Abstract
X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease that is caused by mutations in the ABCD1 gene and characterized by elevated levels of very long-chain fatty acids (VLCFA) in plasma and tissues, with the most pronounced increase in the central nervous system. Virtually all male patients develop adrenal insufficiency and myelopathy (adrenomyeloneuropathy), but a subset develops a fatal cerebral demyelinating disease (known as cerebral ALD). Female patients may also develop myelopathy, but adrenal insufficiency or leukodystrophy are very rare. ALD has been associated with mitochondrial dysfunction, oxidative stress and bioenergetic failure, but the mechanism by which VLCFA accumulation triggers these effects has not been resolved thus far. In this study, we used primary human fibroblasts from normal subjects and ALD patients to investigate whether VLCFA can induce endoplasmic reticulum stress. We show that saturated VLCFA (C26:0) induce endoplasmic reticulum stress in fibroblasts from ALD patients, but not in controls. Furthermore, there is a clear correlation between the chain-length of the fatty acid and the induction of endoplasmic reticulum stress. Exposure of ALD fibroblasts to C26:0, resulted in increased expression of additional endoplasmic reticulum stress markers (EDEM1, GADD34 and CHOP) and in lipoapoptosis. This new insight into the underlying mechanism of VLCFA-induced toxicity is of great importance for the development of a disease modifying treatment for ALD aimed at the normalization of VLCFA levels in tissues.
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19
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Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy. Acta Neuropathol 2017; 133:283-301. [PMID: 28004277 PMCID: PMC5250669 DOI: 10.1007/s00401-016-1655-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 12/09/2016] [Accepted: 12/09/2016] [Indexed: 12/11/2022]
Abstract
The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1− and Abcd1−/Abcd2−/− mice) and X-ALD patient’s fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1−/Abcd2−/− mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated.
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20
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van de Beek MC, Dijkstra IME, Kemp S. Method for Measurement of Peroxisomal Very Long-Chain Fatty Acid Beta-Oxidation and De Novo C26:0 Synthesis Activity in Living Cells Using Stable-Isotope Labeled Docosanoic Acid. Methods Mol Biol 2017; 1595:45-54. [PMID: 28409450 DOI: 10.1007/978-1-4939-6937-1_5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Peroxisomes are present in virtually every eukaryotic cell type with the exception of the mature erythrocyte. In higher eukaryotes, one of the main functions of peroxisomes is lipid metabolism by means of beta-oxidation of very long-chain fatty acids (VLCFA; ≥22 carbon atoms). A dysfunction in peroxisomal VLCFA beta-oxidation results in elevated VLCFA levels in cells, tissue, and plasma. Here, we describe a straightforward and sensitive method to measure peroxisomal beta-oxidation capacity in living cells using stable-isotope labeled docosanoic acid (D3-C22:0).
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Affiliation(s)
- Malu-Clair van de Beek
- Laboratory Genetic Metabolic Diseases (F0-226), Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Inge M E Dijkstra
- Laboratory Genetic Metabolic Diseases (F0-226), Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Stephan Kemp
- Laboratory Genetic Metabolic Diseases (F0-226), Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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21
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Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol 2016; 12:606-15. [PMID: 27312864 DOI: 10.1038/nrendo.2016.90] [Citation(s) in RCA: 180] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
X-Linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, which leads to the accumulation of very long-chain fatty acids in plasma and tissues. Virtually all men with ALD develop adrenal insufficiency and myelopathy. Approximately 60% of men develop progressive cerebral white matter lesions (known as cerebral ALD). However, one cannot identify these individuals until the early changes are seen using brain imaging. Women with ALD also develop myelopathy, but generally at a later age than men and adrenal insufficiency or cerebral ALD are very rare. Owing to the multisystem symptomatology of the disease, patients can be assessed by the paediatrician, general practitioner, endocrinologist or a neurologist. This Review describes current knowledge on the clinical presentation, diagnosis and treatment of ALD, and highlights gaps in our knowledge of the natural history of the disease owing to an absence of large-scale prospective cohort studies. Such studies are necessary for the identification of new prognostic biomarkers to improve care for patients with ALD, which is particularly relevant now that newborn screening for ALD is being introduced.
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Affiliation(s)
- Stephan Kemp
- Department of Pediatrics, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Genetic Metabolic Diseases, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Irene C Huffnagel
- Department of Pediatrics, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Pediatric Neurology, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Gabor E Linthorst
- Endocrinology and Metabolism, Academisch Medisch Centrum, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Ronald J Wanders
- Department of Pediatrics, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Genetic Metabolic Diseases, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Marc Engelen
- Department of Pediatrics, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
- Pediatric Neurology, Academisch Medisch Centrum, University of Amsterdam Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
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van Engen CE, Ofman R, Dijkstra IME, van Goethem TJ, Verheij E, Varin J, Vidaud M, Wanders RJA, Aubourg P, Kemp S, Barbier M. CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids. Biochim Biophys Acta Mol Basis Dis 2016; 1862:1861-70. [PMID: 27425035 DOI: 10.1016/j.bbadis.2016.07.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 07/04/2016] [Accepted: 07/13/2016] [Indexed: 01/08/2023]
Abstract
X-linked adrenoleukodystrophy (ALD) is a severe neurodegenerative disorder caused by the accumulation of very long-chain fatty acids (VLCFA) due to mutations in the ABCD1 gene. The phenotypic spectrum ranges from a fatal cerebral demyelinating disease in childhood (cerebral ALD) to a progressive myelopathy without cerebral involvement in adulthood (adrenomyeloneuropathy). Because ABCD1 mutations have no predictive value with respect to clinical outcome a role for modifier genes was postulated. We report that the CYP4F2 polymorphism rs2108622 increases the risk of developing cerebral ALD in Caucasian patients. The rs2108622 polymorphism (c.1297G>A) results in an amino acid substitution valine for methionine at position 433 (p.V433M). Using cellular models of VLCFA accumulation, we show that p.V433M decreases the conversion of VLCFA into very long-chain dicarboxylic acids by ω-oxidation, a potential escape route for the deficient peroxisomal β-oxidation of VLCFA in ALD. Although p.V433M does not affect the catalytic activity of CYP4F2 it reduces CYP4F2 protein levels markedly. These findings open perspectives for therapeutic interventions in a disease with currently limited treatment options.
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Affiliation(s)
- Catherine E van Engen
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Rob Ofman
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Inge M E Dijkstra
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Tessa Jacobs van Goethem
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Eveline Verheij
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jennifer Varin
- INSERM U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris-Descartes, Sorbonne Paris Cité, Paris, France
| | - Michel Vidaud
- INSERM U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris-Descartes, Sorbonne Paris Cité, Paris, France
| | - Ronald J A Wanders
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Patrick Aubourg
- INSERM U986, Le Kremlin-Bicêtre, Paris, France; Faculté de Médecine, Université Paris-Sud, Assistance Publique des Hôpitaux de Paris, Le Kremlin-Bicêtre, Paris, France
| | - Stephan Kemp
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Schackmann MJA, Ofman R, van Geel BM, Dijkstra IME, van Engelen K, Wanders RJA, Engelen M, Kemp S. Pathogenicity of novel ABCD1 variants: The need for biochemical testing in the era of advanced genetics. Mol Genet Metab 2016; 118:123-7. [PMID: 27067449 DOI: 10.1016/j.ymgme.2016.03.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/29/2016] [Accepted: 03/29/2016] [Indexed: 11/20/2022]
Abstract
X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. In male patients, an increased plasma VLCFA levels in combination with a pathogenic mutation in ABCD1 confirms the diagnosis. Recent studies have shown that many women with ALD also develop myelopathy. Correct diagnosis is important for management including genetic counseling. Diagnosis in women can only be confirmed when VLCFA levels are elevated or when a known pathogenic ABCD1 mutation is identified. However, in 15-20% of women with ALD VLCFA plasma levels are not elevated. Demonstration that a novel sequence variant is pathogenic can be a challenge when VLCFA levels are in the normal range. Here we report two women with a clinical presentation compatible with ALD, an ABCD1 variation (p.Arg17His and p.Ser358Pro) of unknown significance, but with normal VLCFA levels. We developed a diagnostic test that is based on generating clonal cell lines that express only one of the two alleles. Subsequent biochemical studies enabled us to show that the two sequence variants were not pathogenic, thereby excluding the diagnosis ALD in these women. We conclude that the clonal approach is an important addition to the existing diagnostic array.
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Affiliation(s)
- Martin J A Schackmann
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Rob Ofman
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Björn M van Geel
- Department of Neurology, Medical Center Alkmaar, Alkmaar, The Netherlands
| | - Inge M E Dijkstra
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Klaartje van Engelen
- Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
| | - Ronald J A Wanders
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Marc Engelen
- Departments of Pediatrics and Pediatric Neurology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Stephan Kemp
- Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Departments of Pediatrics and Pediatric Neurology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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24
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Ahmed MA, Kartha RV, Brundage RC, Cloyd J, Basu C, Carlin BP, Jones RO, Moser AB, Fatemi A, Raymond GV. A model-based approach to assess the exposure-response relationship of Lorenzo's oil in adrenoleukodystrophy. Br J Clin Pharmacol 2016; 81:1058-66. [PMID: 26836218 DOI: 10.1111/bcp.12897] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 01/26/2016] [Accepted: 02/01/2016] [Indexed: 11/30/2022] Open
Abstract
AIMS X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder, most commonly affecting boys, associated with increased very long chain fatty acids (C26:0) in all tissues, causing cerebral demyelination and adrenocortical insufficiency. Certain monounsaturated long chain fatty acids including oleic and erucic acids, known as Lorenzo's oil (LO), lower plasma C26:0 levels. The aims of this study were to characterize the effect of LO administration on plasma C26:0 concentrations and to determine whether there is an association between plasma concentrations of erucic acid or C26:0 and the likelihood of developing brain MRI abnormalities in asymptomatic boys. METHODS Non-linear mixed effects modelling was performed on 2384 samples collected during an open label single arm trial. The subjects (n = 104) were administered LO daily at ~2-3 mg kg(-1) with a mean follow-up of 4.88 ± 2.76 years. The effect of erucic acid exposure on plasma C26:0 concentrations was characterized by an inhibitory fractional Emax model. A Weibull model was used to characterize the time-to-developing MRI abnormality. RESULTS The population estimate for the fractional maximum reduction of C26:0 plasma concentrations was 0.76 (bootstrap 95% CI 0.73, 0.793). Our time-to-event analyses showed that every mg l(-1) increase in time-weighted average of erucic acid and C26:0 plasma concentrations was, respectively, associated with a 3.7% reduction and a 753% increase in the hazard of developing MRI abnormality. However, the results were not significant (P = 0.5344, 0.1509, respectively). CONCLUSIONS LO administration significantly reduces the abnormally high plasma C26:0 concentrations in X-ALD patients. Further studies to evaluate the effect of LO on the likelihood of developing brain MRI abnormality are warranted.
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Affiliation(s)
- Mariam A Ahmed
- Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.,Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.,Department of Pharmacy Practice, Helwan University, Cairo, Egypt
| | - Reena V Kartha
- Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.,Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - Richard C Brundage
- Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.,Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - James Cloyd
- Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.,Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - Cynthia Basu
- Division of Biostatistics, University of Minnesota, Minneapolis, MN
| | - Bradley P Carlin
- Division of Biostatistics, University of Minnesota, Minneapolis, MN
| | - Richard O Jones
- Division of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD
| | - Ann B Moser
- Peroxisomal Diseases Laboratory, Kennedy Krieger Institute, Baltimore, MD
| | - Ali Fatemi
- Genetics Laboratories, Kennedy Krieger Institute, Baltimore, MD
| | - Gerald V Raymond
- Department of Neurology, University of Minnesota, Minneapolis, MN, USA
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Sivachenko A, Gordon HB, Kimball SS, Gavin EJ, Bonkowsky JL, Letsou A. Neurodegeneration in a Drosophila model of adrenoleukodystrophy: the roles of the Bubblegum and Double bubble acyl-CoA synthetases. Dis Model Mech 2016; 9:377-87. [PMID: 26893370 PMCID: PMC4852500 DOI: 10.1242/dmm.022244] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 02/17/2016] [Indexed: 12/21/2022] Open
Abstract
Debilitating neurodegenerative conditions with metabolic origins affect millions of individuals worldwide. Still, for most of these neurometabolic disorders there are neither cures nor disease-modifying therapies, and novel animal models are needed for elucidation of disease pathology and identification of potential therapeutic agents. To date, metabolic neurodegenerative disease has been modeled in animals with only limited success, in part because existing models constitute analyses of single mutants and have thus overlooked potential redundancy within metabolic gene pathways associated with disease. Here, we present the first analysis of a very-long-chain acyl-CoA synthetase (ACS) double mutant. We show that the Drosophila bubblegum(bgm) and double bubble(dbb) genes have overlapping functions, and that the consequences of double knockout of both bubblegum and double bubble in the fly brain are profound, affecting behavior and brain morphology, and providing the best paradigm to date for an animal model of adrenoleukodystrophy (ALD), a fatal childhood neurodegenerative disease associated with the accumulation of very-long-chain fatty acids. Using this more fully penetrant model of disease to interrogate brain morphology at the level of electron microscopy, we show that dysregulation of fatty acid metabolism via disruption of ACS function in vivois causal of neurodegenerative pathologies that are evident in both neuronal cells and their supporting cell populations, and leads ultimately to lytic cell death in affected areas of the brain. Finally, in an extension of our model system to the study of human disease, we describe our identification of an individual with leukodystrophy who harbors a rare mutation in SLC27a6(encoding a very-long-chain ACS), a human homolog of bgm and dbb.
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Affiliation(s)
- Anna Sivachenko
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Hannah B Gordon
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Suzanne S Kimball
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Erin J Gavin
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Joshua L Bonkowsky
- Department of Pediatrics, University of Utah, Salt Lake City, UT 84112, USA
| | - Anthea Letsou
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
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MicroRNA Profiling Identifies miR-196a as Differentially Expressed in Childhood Adrenoleukodystrophy and Adult Adrenomyeloneuropathy. Mol Neurobiol 2016; 54:1392-1403. [PMID: 26843114 DOI: 10.1007/s12035-016-9746-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 01/22/2016] [Indexed: 01/18/2023]
Abstract
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene, leading to a defect in the peroxisomal adrenoleukodystrophy protein (ALDP), which inhibits the β-oxidation of very long chain fatty acids (VLCFAs). It is a complex disease where the same mutation in the peroxisomal ABCD1 can lead to clinically diverse phenotypes ranging from the fatal disorder of cerebral ALD (cALD) to mild adult disorder of adrenomyeloneuropathy (AMN). This suggests a role of epigenetic factors/modifier genes in disease progression of X-ALD which is not understood at present. To examine the possible role of microRNA (miRNA) in X-ALD disease mechanisms for differences in cALD and AMN phenotype, we profiled 1008 known miRNA in cALD, AMN, and normal human skin fibroblasts using miScript miRNA PCR array (Qiagen) and selected miRNAs which had differential expression in cALD and AMN fibroblasts. Eleven miRNA which were differentially regulated in cALD and AMN fibroblasts were identified. miR-196a showed a significant differential expression between cALD and AMN and is further characterized for target gene regulation. The predicted role of miR-196a in inhibition of inflammatory signaling factors (IKKα and IKKβ) and ELOVL1 expression suggests the pathological role of altered expression of miR-196a. This study indicates that miR-196a participated in differential regulation of ELOVL1 and inflammatory response between cALD as compared to AMN and may be a possible biomarker to differentiate between cALD and AMN.
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Morita M, Kawamichi M, Shimura Y, Kawaguchi K, Watanabe S, Imanaka T. Brain microsomal fatty acid elongation is increased in abcd1-deficient mouse during active myelination phase. Metab Brain Dis 2015; 30:1359-67. [PMID: 26108493 DOI: 10.1007/s11011-015-9701-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 06/12/2015] [Indexed: 10/23/2022]
Abstract
The dysfunction of ABCD1, a peroxisomal ABC protein, leads to the perturbation of very long chain fatty acid (VLCFA) metabolism and is the cause of X-linked adrenoleukodystrophy. Abcd1-deficient mice exhibit an accumulation of saturated VLCFAs, such as C26:0, in all tissues, especially the brain. The present study sought to measure microsomal fatty acid elongation activity in the brain of wild-type (WT) and abcd1-deficient mice during the course of development. The fatty acid elongation activity in the microsomal fraction was measured by the incorporation of [2-(14)C]malonyl-CoA into fatty acids in the presence of C16:0-CoA or C20:0-CoA. Cytosolic fatty acid synthesis activity was completely inhibited by the addition of N-ethylmaleimide (NEM). The microsomal fatty acid elongation activity in the brain was significantly high at 3 weeks after birth and decreased substantially at 3 months after birth. Furthermore, we detected two different types of microsomal fatty acid elongation activity by using C16:0-CoA or C20:0-CoA as the substrate and found the activity toward C20:0-CoA in abcd1-deficient mice was higher than the WT 3-week-old animals. These results suggest that during the active myelination phase the microsomal fatty acid elongation activity is stimulated in abcd1-deficient mice, which in turn perturbs the lipid composition in myelin.
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Affiliation(s)
- Masashi Morita
- Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Misato Kawamichi
- Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yusuke Shimura
- Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Kosuke Kawaguchi
- Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Shiro Watanabe
- Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Tsuneo Imanaka
- Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
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Senanayake VK, Jin W, Mochizuki A, Chitou B, Goodenowe DB. Metabolic dysfunctions in multiple sclerosis: implications as to causation, early detection, and treatment, a case control study. BMC Neurol 2015; 15:154. [PMID: 26311235 PMCID: PMC4549881 DOI: 10.1186/s12883-015-0411-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Accepted: 08/18/2015] [Indexed: 12/20/2022] Open
Abstract
Background Biochemical changes associated with multiple sclerosis (MS), and its various clinical forms have not been characterized well. Therefore, we investigated the biochemistry of MS in relation to its natural history using targeted lipidomics platforms. Methods Cross-sectional serum samples from 24 secondary progressive (SPMS), 100 relapsing remitting (RRMS), 19 primary progressive MS (PPMS), and 55 age-matched control subjects were analyzed by flow injection tandem mass spectrometry for very long chain fatty acid (VLCFA) containing phosphatidyl ethanolamines (PtdEtn), plasmalogen ethanolamines (PlsEtn) and for novel anti-inflammatory gastrointestinal tract acids (GTAs). Changes in analyte levels relative to healthy controls were correlated with the disease stage and disease duration. Results RRMS subjects having <13 years disease duration had elevated levels (p < 0.05) of anti-inflammatory metabolites (GTAs) and normal levels (p > 0.05) of mitochondrial stress biomarkers (VLCFA-PtdEtn), compared to controls. SPMS subjects had statistically similar levels of anti-inflammatory metabolites (GTAs), elevated mitochondrial stress metabolites (VLCFA-PtdEtn) and elevated peroxisomal metabolites (PlsEtn) compared to controls (p < 0.05). RRMS subjects with > = 13 years disease duration exhibited metabolic profiles intermediate between short-duration RRMS and SPMS, based on statistical significance. Therefore, RRMS cohort appear to comprise of two metabolically distinct subpopulations. The key clinical discriminator of these two groups was disease duration. PPMS patients exhibited metabolic profiles distinct from RRMS and SPMS. Conclusions These data indicate that inflammation and mitochondrial stress are intricately involved in the etiology of MS and that progression in MS can potentially be monitored using serum metabolic biomarkers.
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Affiliation(s)
- Vijitha K Senanayake
- Phenomenome Discoveries Inc, 204-407 Downey Road, Saskatoon, SK, S7N 4L8, Canada
| | - Wei Jin
- Phenomenome Discoveries Inc, 204-407 Downey Road, Saskatoon, SK, S7N 4L8, Canada
| | - Asuka Mochizuki
- Phenomenome Discoveries Inc, 204-407 Downey Road, Saskatoon, SK, S7N 4L8, Canada
| | - Bassirou Chitou
- Phenomenome Discoveries Inc, 204-407 Downey Road, Saskatoon, SK, S7N 4L8, Canada
| | - Dayan B Goodenowe
- Phenomenome Discoveries Inc, 204-407 Downey Road, Saskatoon, SK, S7N 4L8, Canada.
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Schackmann MJ, Ofman R, Dijkstra IM, Wanders RJ, Kemp S. Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis. Biochim Biophys Acta Mol Cell Biol Lipids 2015; 1851:231-7. [DOI: 10.1016/j.bbalip.2014.12.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 12/05/2014] [Indexed: 10/24/2022]
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Baarine M, Beeson C, Singh A, Singh I. ABCD1 deletion-induced mitochondrial dysfunction is corrected by SAHA: implication for adrenoleukodystrophy. J Neurochem 2015; 133:380-96. [PMID: 25393703 DOI: 10.1111/jnc.12992] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 10/09/2014] [Accepted: 11/07/2014] [Indexed: 01/09/2023]
Abstract
X-linked Adrenoleukodystrophy (X-ALD), an inherited peroxisomal metabolic neurodegenerative disorder, is caused by mutations/deletions in the ATP-binding cassette transporter (ABCD1) gene encoding peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). Metabolic dysfunction in X-ALD is characterized by the accumulation of very long chain fatty acids ≥ C22:0) in the tissues and plasma of patients. Here, we investigated the mitochondrial status following deletion of ABCD1 in B12 oligodendrocytes and U87 astrocytes. This study provides evidence that silencing of peroxisomal protein ABCD1 produces structural and functional perturbations in mitochondria. Activities of electron transport chain-related enzymes and of citric acid cycle (TCA cycle) were reduced; mitochondrial redox status was dysregulated and the mitochondrial membrane potential was disrupted following ABCD1 silencing. A greater reduction in ATP levels and citrate synthase activities was observed in oligodendrocytes as compared to astrocytes. Furthermore, most of the mitochondrial perturbations induced by ABCD1 silencing were corrected by treating cells with suberoylanilide hydroxamic acid, an Histone deacetylase inhibitor. These observations indicate a novel relationship between peroxisomes and mitochondria in cellular homeostasis and the importance of intact peroxisomes in relation to mitochondrial integrity and function in the cell types that participate in the pathobiology of X-ALD. These observations suggest suberoylanilide hydroxamic acid as a potential therapy for X-ALD. Schematic description of the effects of loss of peroxisomal ATP-binding cassette transporter D1 (ABCD1) gene on cellular Redox and mitochondrial activities and their correction by suberoylanilide hydroxamic acid (SAHA) treatment. Pathogenomic accumulation of very long chain fatty acids (VLCFA) as a result of loss of ABCD1 leads to dysfunctions of mitochondrial biogenesis and its activities. Treatment with SAHA corrects mitochondrial dysfunctions. These studies describe unique cooperation between mitochondria and peroxisome for cellular activities.
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Affiliation(s)
- Mauhamad Baarine
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA
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Abcd2 is a strong modifier of the metabolic impairments in peritoneal macrophages of ABCD1-deficient mice. PLoS One 2014; 9:e108655. [PMID: 25255441 PMCID: PMC4177892 DOI: 10.1371/journal.pone.0108655] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 08/25/2014] [Indexed: 02/08/2023] Open
Abstract
The inherited peroxisomal disorder X-linked adrenoleukodystrophy (X-ALD), associated with neurodegeneration and inflammatory cerebral demyelination, is caused by mutations in the ABCD1 gene encoding the peroxisomal ATP-binding cassette (ABC) transporter ABCD1 (ALDP). ABCD1 transports CoA-esters of very long-chain fatty acids (VLCFA) into peroxisomes for degradation by β-oxidation; thus, ABCD1 deficiency results in VLCFA accumulation. The closest homologue, ABCD2 (ALDRP), when overexpressed, compensates for ABCD1 deficiency in X-ALD fibroblasts and in Abcd1-deficient mice. Microglia/macrophages have emerged as important players in the progression of neuroinflammation. Human monocytes, lacking significant expression of ABCD2, display severely impaired VLCFA metabolism in X-ALD. Here, we used thioglycollate-elicited primary mouse peritoneal macrophages (MPMΦ) from Abcd1 and Abcd2 single- and double-deficient mice to establish how these mutations affect VLCFA metabolism. By quantitative RT-PCR, Abcd2 mRNA was about half as abundant as Abcd1 mRNA in wild-type and similarly abundant in Abcd1-deficient MPMΦ. VLCFA (C26∶0) accumulated about twofold in Abcd1-deficient MPMΦ compared with wild-type controls, as measured by gas chromatography-mass spectrometry. In Abcd2-deficient macrophages VLCFA levels were normal. However, upon Abcd1/Abcd2 double-deficiency, VLCFA accumulation was markedly increased (sixfold) compared with Abcd1-deficient MPMΦ. Elovl1 mRNA, encoding the rate-limiting enzyme for elongation of VLCFA, was equally abundant across all genotypes. Peroxisomal β-oxidation of C26∶0 amounted to 62% of wild-type activity in Abcd1-deficient MPMΦ and was significantly more impaired (29% residual activity) upon Abcd1/Abcd2 double-deficiency. Single Abcd2 deficiency did not significantly compromise β-oxidation of C26∶0. Thus, the striking accumulation of VLCFA in double-deficient MPMΦ compared with single Abcd1 deficiency was due to the loss of ABCD2-mediated, compensatory transport of VLCFA into peroxisomes. We propose that moderate endogenous expression of Abcd2 in Abcd1-deficient murine macrophages prevents the severe metabolic phenotype observed in human X-ALD monocytes, which lack appreciable expression of ABCD2. This supports upregulation of ABCD2 as a therapeutic concept in X-ALD.
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Berger J, Forss-Petter S, Eichler FS. Pathophysiology of X-linked adrenoleukodystrophy. Biochimie 2013; 98:135-42. [PMID: 24316281 PMCID: PMC3988840 DOI: 10.1016/j.biochi.2013.11.023] [Citation(s) in RCA: 155] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 11/22/2013] [Indexed: 12/26/2022]
Abstract
Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset, leading to death within a few years, to adults remaining pre-symptomatic through more than five decades. There is no general genotype–phenotype correlation in X-ALD. The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy. In about 60% of male X-ALD patients, either in childhood (35–40%) or in adulthood (20%), an initial, clinically silent, myelin destabilization results in conversion to a devastating, rapidly progressive form of cerebral inflammatory demyelination. Here, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur. Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon–glial interactions seem pertinent to the dying-back axonopathy. Various dynamic mechanisms may underlie the initiation of inflammation, the altered immune reactivity, the propagation of inflammation, as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation. An improved understanding of the molecular mechanisms involved in these events is required for the development of urgently needed therapeutics.
Adrenomyeloneuropathy (AMN) is proposed to be the core syndrome of X-ALD. The cerebral inflammatory demyelinating form of X-ALD is independent of AMN. The same genetic basis but fundamentally different pathomechanisms lead to AMN and cerebral ALD. Genetic, epigenetic and environmental factors modulate onset and severity of AMN and cerebral ALD.
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Affiliation(s)
- J Berger
- Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
| | - S Forss-Petter
- Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria
| | - F S Eichler
- Department for Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street ACC 708, Boston, MA 02114, USA
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Singh J, Khan M, Pujol A, Baarine M, Singh I. Histone deacetylase inhibitor upregulates peroxisomal fatty acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells. PLoS One 2013; 8:e70712. [PMID: 23923017 PMCID: PMC3724778 DOI: 10.1371/journal.pone.0070712] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 06/26/2013] [Indexed: 11/22/2022] Open
Abstract
In X-ALD, mutation/deletion of ALD gene (ABCD1) and the resultant very long chain fatty acid (VLCFA) derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD). The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal β-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs) (1 and 3) in both cell types. However, higher induction of ELOVL's in Abcd1-deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL) and cell survival (phospho-Erk1/2) proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid) leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial-caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD.
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Affiliation(s)
- Jaspreet Singh
- Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Mushfiquddin Khan
- Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Aurora Pujol
- Neurometabolic Diseases Laboratory, Institute of Neuropathology, Bellvitge Institute for Biomedical Research (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
- Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Mauhamad Baarine
- Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Inderjit Singh
- Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America
- * E-mail:
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Abstract
The peroxisomal disorders represent a group of genetic diseases in man in which there is an impairment in one or more peroxisomal functions. The peroxisomal disorders are subdivided into three subgroups comprising: (1) the peroxisome biogenesis disorders (PBDs); (2) the single peroxisomal (enzyme-) protein deficiencies; and (3) the single peroxisomal substrate transport deficiencies. The PBD group comprises four different disorders that include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). ZS, NALD, and IRD are clearly distinct from RCDP and are usually referred to as the Zellweger spectrum with ZS being the most severe, and IRD the less severe disorder, with sometimes onset in adulthood. The single peroxisomal enzyme deficiency group comprises seven different disorders, of which D-bifunctional protein and phytanoyl-CoA hydroxylase (adult Refsum disease) deficiencies are the most frequent. The single peroxisomal substrate transport deficiency group consists of only one disease, X-linked adrenoleukodystrophy. It is the purpose of this chapter to describe the current state of knowledge about the clinical, biochemical, cellular, and molecular aspects of peroxisomal diseases, and to provide guidelines for their post- and prenatal diagnosis. Therapeutic interventions are mostly limited to X-linked adrenoleukodystrophy.
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Affiliation(s)
- Patrick Aubourg
- Department of Pediatric Neurology, INSERM UM745, University Paris-Descartes, Hôpital Bicêtre-Paris Sud, Paris, France.
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Kemp S, Berger J, Aubourg P. X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta Mol Basis Dis 2012; 1822:1465-74. [DOI: 10.1016/j.bbadis.2012.03.012] [Citation(s) in RCA: 191] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Revised: 03/08/2012] [Accepted: 03/20/2012] [Indexed: 12/28/2022]
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Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJA, Aubourg P, Poll-The BT. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis 2012; 7:51. [PMID: 22889154 PMCID: PMC3503704 DOI: 10.1186/1750-1172-7-51] [Citation(s) in RCA: 363] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 06/11/2012] [Indexed: 12/21/2022] Open
Abstract
X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids (VLCFA; ≥C22). A defect in ALDP results in elevated levels of VLCFA in plasma and tissues. The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. The majority of heterozygous females will develop symptoms by the age of 60 years. In individual patients the disease course remains unpredictable. This review focuses on the diagnosis and management of patients with X-ALD and provides a guideline for clinicians that encounter patients with this highly complex disorder.
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Affiliation(s)
- Marc Engelen
- Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Singh J, Khan M, Singh I. HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes. J Lipid Res 2011; 52:2056-69. [PMID: 21891797 DOI: 10.1194/jlr.m017491] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). The consistent metabolic abnormality in all forms of X-ALD is an inherited defect in the peroxisomal β-oxidation of very long chain FAs (VLCFAs >C22:0) and the resultant pathognomic accumulation of VLCFA. The accumulation of VLCFA leads to a neuroinflammatory disease process associated with demyelination of the cerebral white matter. The present study underlines the importance of a potent histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA) in inducing the expression of ABCD2 [adrenoleukodystrophy-related protein (ALDRP)], and normalizing the peroxisomal β-oxidation, as well as the saturated and monounsaturated VLCFAs in cultured human skin fibroblasts of X-ALD patients. The expression of ELOVL1, the single elongase catalyzing the synthesis of both saturated VLCFA (C26:0) and monounsaturated VLCFA (C26:1), was also reduced by SAHA treatment. In addition, using Abcd1/Abcd2-silenced mouse primary astrocytes, we also examined the effects of SAHA in VLCFA-induced inflammatory response. SAHA treatment decreased the inflammatory response as expression of inducible nitric oxide synthase, inflammatory cytokine, and activation of NF-κB in Abcd1/Abcd2-silenced mouse primary astrocytes was reduced. These observations indicate that SAHA corrects both the metabolic disease of VLCFA as well as secondary inflammatory disease; therefore, it may be an ideal drug candidate to be tested for X-ALD therapy in humans.
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Affiliation(s)
- Jaspreet Singh
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
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Terre'Blanche G, van der Walt MM, Bergh JJ, Mienie LJ. Treatment of an adrenomyeloneuropathy patient with Lorenzo's oil and supplementation with docosahexaenoic acid--a case report. Lipids Health Dis 2011; 10:152. [PMID: 21871076 PMCID: PMC3177782 DOI: 10.1186/1476-511x-10-152] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Accepted: 08/26/2011] [Indexed: 11/11/2022] Open
Abstract
This is a case report of adrenomyeloneuropathy (AMN), the adult variant of adrenoleukodystryphy (ALD). The diagnoses in the patient, aged 34, was confirmed via increased serum very long chain fatty acid concentration (VLCFA). Treatment started with the cholesterol lowering drug, atorvastatin, followed by add-on therapy with Lorenzo's oil (LO) and finally supplementation with docosahexaenoic acid (DHA). The magnetic resonance imaging (MRI) scan of the AMN patient before DHA treatment, already showed abnormal white matter in the brain. Although the MRI showed no neurological improvement after 6 months of DHA treatment, no selective progression of demyelination was detected in the AMN patient. Contrary to what was expected, LO failed to sustain or normalize the VLCFA levels or improve clinical symptoms. It was however, shown that DHA supplementation in addition to LO, increased DHA levels in both plasma and red blood cells (RBC). Additionally, the study showed evidence that the elongase activity in the elongation of eicosapentaenoic acid (EPA) to docosapentaenoic acid (DPA) might have been significantly compromised, due to the increased DHA levels.
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Affiliation(s)
- Gisella Terre'Blanche
- Pharmaceutical Chemistry, Unit for Drug Research and Development, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
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Faust PL, Kaye EM, Powers JM. Myelin lesions associated with lysosomal and peroxisomal disorders. Expert Rev Neurother 2010; 10:1449-66. [PMID: 20819015 DOI: 10.1586/ern.10.127] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Abnormalities of myelin are common in lysosomal and peroxisomal disorders. Most display a primary loss of myelin in which the myelin sheath and/or oligodendrocytes are selectively targeted by diverse pathogenetic processes. The most severe and, hence, clinically relevant are heritable diseases predominantly of infants and children, the leukodystrophies: metachromatic, globoid cell (Krabbe disease) and adreno-leukodystrophy. Our still limited understanding of these diseases has derived from multiple sources: originally, neurological-neuropathologic-neurochemical correlative studies of the natural disease in humans or other mammals, which has been enhanced by more sophisticated and contemporary techniques of cell and molecular biology. Transgenic mouse models seem to be the most promising methodology, allowing the examination of the cellular role of lysosomes and peroxisomes for formation and maintenance of both myelin and axons, and providing initial platforms to evaluate therapies. Treatment options are woefully inadequate and in their nascent stages, but still inspire some hope for the future.
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Affiliation(s)
- Phyllis L Faust
- Department of Pathology and Cell Biology, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
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41
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Abstract
X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is characterized by the accumulation of very long-chain fatty acids (VLCFA; >C22) in plasma and tissues. X-ALD is caused by mutations in the ABCD1 gene encoding ALDP, an adenosine triphosphate (ATP)-binding-cassette (ABC) transporter located in the peroxisomal membrane. In this paper, we describe the current knowledge on the function of ALDP, its role in peroxisomal VLCFA beta-oxidation and the consequences of a defect in ALDP on VLCFA metabolism. Furthermore, we pay special attention to the role of the VLCFA elongation system in VLCFA homeostasis, with elongation of very long-chain fatty acids like-1 (ELOVL1) as key player, and its relevance to X-ALD.
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Affiliation(s)
- Stephan Kemp
- Academic Medical Center, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Departments of Pediatrics/Emma Children's Hospital and Clinical Chemistry, Amsterdam, the Netherlands.
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42
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Van Veldhoven PP. Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. J Lipid Res 2010; 51:2863-95. [PMID: 20558530 DOI: 10.1194/jlr.r005959] [Citation(s) in RCA: 256] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
In humans, peroxisomes harbor a complex set of enzymes acting on various lipophilic carboxylic acids, organized in two basic pathways, alpha-oxidation and beta-oxidation; the latter pathway can also handle omega-oxidized compounds. Some oxidation products are crucial to human health (primary bile acids and polyunsaturated FAs), whereas other substrates have to be degraded in order to avoid neuropathology at a later age (very long-chain FAs and xenobiotic phytanic acid and pristanic acid). Whereas total absence of peroxisomes is lethal, single peroxisomal protein deficiencies can present with a mild or severe phenotype and are more informative to understand the pathogenic factors. The currently known single protein deficiencies equal about one-fourth of the number of proteins involved in peroxisomal FA metabolism. The biochemical properties of these proteins are highlighted, followed by an overview of the known diseases.
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Affiliation(s)
- Paul P Van Veldhoven
- Katholieke Universiteit Leuven, Department of Molecular Cell Biology, LIPIT, Campus Gasthuisberg, Herestraat, Leuven, Belgium.
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43
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Ofman R, Dijkstra IME, van Roermund CWT, Burger N, Turkenburg M, van Cruchten A, van Engen CE, Wanders RJA, Kemp S. The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy. EMBO Mol Med 2010; 2:90-7. [PMID: 20166112 PMCID: PMC3377275 DOI: 10.1002/emmm.201000061] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). X-ALD is characterized by the accumulation of very long-chain fatty acids (VLCFA; ≥C24) in plasma and tissues. In this manuscript we provide insight into the pathway underlying the elevated levels of C26:0 in X-ALD. ALDP transports VLCFacyl-CoA across the peroxisomal membrane. A deficiency in ALDP impairs peroxisomal β-oxidation of VLCFA but also raises cytosolic levels of VLCFacyl-CoA which are substrate for further elongation. We identify ELOVL1 (elongation of very-long-chain-fatty acids) as the single elongase catalysing the synthesis of both saturated VLCFA (C26:0) and mono-unsaturated VLCFA (C26:1). ELOVL1 expression is not increased in X-ALD fibroblasts suggesting that increased levels of C26:0 result from increased substrate availability due to the primary deficiency in ALDP. Importantly, ELOVL1 knockdown reduces elongation of C22:0 to C26:0 and lowers C26:0 levels in X-ALD fibroblasts. Given the likely pathogenic effects of high C26:0 levels, our findings highlight the potential of modulating ELOVL1 activity in the treatment of X-ALD.
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Affiliation(s)
- Rob Ofman
- Academic Medical Center, Departments of Pediatrics and Clinical Chemistry, University of Amsterdam, The Netherlands
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44
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Fourcade S, Ruiz M, Guilera C, Hahnen E, Brichta L, Naudi A, Portero-Otín M, Dacremont G, Cartier N, Wanders R, Kemp S, Mandel JL, Wirth B, Pamplona R, Aubourg P, Pujol A. Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy. Hum Mol Genet 2010; 19:2005-14. [PMID: 20179078 DOI: 10.1093/hmg/ddq082] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
X-linked adrenoleukodystrophy (X-ALD) is a fatal, axonal demyelinating, neurometabolic disease. It results from the functional loss of a member of the peroxisomal ATP-binding cassette transporter subfamily D (ABCD1), which is involved in the metabolism of very long-chain fatty acids (VLCFA). Oxidative damage of proteins caused by excess of the hexacosanoic acid, the most prevalent VLCFA accumulating in X-ALD, is an early event in the neurodegenerative cascade. We demonstrate here that valproic acid (VPA), a widely used anti-epileptic drug with histone deacetylase inhibitor properties, induced the expression of the functionally overlapping ABCD2 peroxisomal transporter. VPA corrected the oxidative damage and decreased the levels of monounsaturated VLCFA (C26:1 n-9), but not saturated VLCFA. Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse model of X-ALD. A 6-month pilot trial of VPA in X-ALD patients resulted in reversion of the oxidative damage of proteins in peripheral blood mononuclear cells. Thus, we propose VPA as a promising novel therapeutic approach that warrants further clinical investigation in X-ALD.
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Affiliation(s)
- Stéphane Fourcade
- Neurometabolic Disease Lab, Institut of Neuropathology, Institut d'Investigació Biomèdica de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
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Ivanova PT, Milne SB, Brown HA. Identification of atypical ether-linked glycerophospholipid species in macrophages by mass spectrometry. J Lipid Res 2009; 51:1581-90. [PMID: 19965583 DOI: 10.1194/jlr.d003715] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
A large scale profiling and analysis of glycerophospholipid species in macrophages has facilitated the identification of several rare and atypical glycerophospholipid species. By using liquid chromatography tandem mass spectrometry and comparison of the elution and fragmentation properties of the rare lipids to synthetic standards, we were able to identify an array of ether-linked phosphatidylinositols (PIs), phosphatidic acids, phosphatidylserines (PSs), very long chain phosphatidylethanolamines (PEs), and phosphatidylcholines (PCs) as well as phosphatidylthreonines (PTs) and a wide collection of odd carbon fatty acid-containing phospholipids in macrophages. A comprehensive qualitative analysis of glycerophospholipids from different macrophage cells was conducted. During the phospholipid profiling of the macrophage-like RAW 264.7 cells, we identified dozens of rare or previously uncharacterized phospholipids, including ether-linked PIs, PSs, and glycerophosphatidic acids, PTs, and PCs and PTs containing very long polyunsaturated fatty acids. Additionally, large numbers of phospholipids containing at least one odd carbon fatty acid were identified. Using the same methodology, we also identified many of the same species of glycerophospholipids in resident peritoneal macrophages, foam cells, and murine bone marrow derived macrophages.
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Affiliation(s)
- Pavlina T Ivanova
- Department of Pharmacology and Chemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Pillai BK, Jasuja R, Simard JR, Hamilton JA. Fast diffusion of very long chain saturated fatty acids across a bilayer membrane and their rapid extraction by cyclodextrins: implications for adrenoleukodystrophy. J Biol Chem 2009; 284:33296-304. [PMID: 19801636 PMCID: PMC2785172 DOI: 10.1074/jbc.m109.043737] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2009] [Revised: 09/28/2009] [Indexed: 12/24/2022] Open
Abstract
Abnormalities in the transport of saturated very long chain fatty acids (VLCFA; >C18:0) contribute to their toxic levels in peroxisomal disorders of fatty acid metabolism, such as adrenoleukodystrophy and adrenomyeloneuropathy. We previously showed that VLCFA desorb much slower than normal dietary fatty acids from both albumin and protein-free lipid bilayers. The important step of transbilayer movement (flip-flop) was not measured directly as a consequence of this very slow desorption from donors, and the extremely low aqueous solubility of VLCFA precludes addition of unbound VLCFA to lipid membranes. We have overcome these limitations using methyl-beta-cyclodextrin to solubilize VLCFA for rapid delivery to "acceptor" phosphatidylcholine vesicles (small and large unilamellar) and to cells. VLCFA binding was monitored in real time with the fluorescent probe fluorescein-labeled phosphatidylethanolamine in the outer membrane leaflet, and entrapped pyranine was used to detect flip-flop across the membrane. The upper limit of the rate of flip-flop across the membrane was independent of temperature and media viscosity and was similar for model raft and non-raft membranes as well as living cells. We further showed that cyclodextrins can extract VLCFA rapidly (within seconds) from vesicles and cells, which have implications for the mechanism and potential alternative approaches to treat adrenoleukodystrophy. Because VLCFA diffuse through the lipid bilayer, proteins may not be required for their transport across the peroxisomal membrane.
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Affiliation(s)
| | - Ravi Jasuja
- Section of Endocrinology, Diabetes and Nutrition, and
| | - Jeffrey R. Simard
- From the Department of Biophysics and Physiology
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine and
| | - James A. Hamilton
- From the Department of Biophysics and Physiology
- the Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02118
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47
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Abstract
Peroxisomes are ubiquitous organelles with multiple metabolic functions, but their precise role in the maintenance of tissues is not well understood. All diseases caused by partial or complete peroxisome dysfunction are characterized by a variety of neurological abnormalities, underscoring the importance of peroxisomes in nervous tissue. The interrelationship between metabolic abnormalities, histological changes, and clinical signs in these peroxisomal diseases has not yet been clarified. During the past decade, a more systematic study of the consequences of peroxisome dysfunction was possible through the generation of knockout mice with generalized or conditional inactivation of peroxisomal proteins. It appears that peroxisomes are necessary for the preservation of axonal integrity and for the formation and maintenance of myelin.
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Affiliation(s)
- Myriam Baes
- Laboratory of Cell Metabolism, KU Leuven, Leuven, Belgium.
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48
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Arnauld S, Fidaleo M, Clémencet MC, Chevillard G, Athias A, Gresti J, Wanders RJ, Latruffe N, Nicolas-Francès V, Mandard S. Modulation of the hepatic fatty acid pool in peroxisomal 3-ketoacyl-CoA thiolase B-null mice exposed to the selective PPARalpha agonist Wy14,643. Biochimie 2009; 91:1376-86. [DOI: 10.1016/j.biochi.2009.09.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2009] [Accepted: 09/14/2009] [Indexed: 11/16/2022]
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Pastural E, Ritchie S, Lu Y, Jin W, Kavianpour A, Khine Su-Myat K, Heath D, Wood PL, Fisk M, Goodenowe DB. Novel plasma phospholipid biomarkers of autism: mitochondrial dysfunction as a putative causative mechanism. Prostaglandins Leukot Essent Fatty Acids 2009; 81:253-64. [PMID: 19608392 DOI: 10.1016/j.plefa.2009.06.003] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Revised: 06/12/2009] [Accepted: 06/15/2009] [Indexed: 12/30/2022]
Abstract
Autism is a neurological disorder that manifests as noticeable behavioral and developmental abnormalities predominantly in males between the ages of 2 and 10. Although the genetics, biochemistry and neuropathology of this disease have been extensively studied, underlying causal factors to this disease have remained elusive. Using a longitudinal trial design in which three plasma samples were collected from 15 autistic and 12 non-autistic age-matched controls over the course of 1 year, universal and unambiguous alterations in lipid metabolism were observed. Biomarkers of fatty acid elongation and desaturation (poly-unsaturated long chain fatty acids (PUFA) and/or saturated very long chain fatty acids (VLCFA)-containing ethanolamine phospholipids) were statistically elevated in all autistic subjects. In all 8 of the affected/non-affected sibling pairs, the affected sibling had higher levels of these biomarkers than the unaffected sibling. Exposure of neurons, astrocytes and hepatocytes in vitro to elevated extracellular glutamate levels resulted in lipid biomarker changes indistinguishable from those observed in autistic subjects. Glutamate stress also resulted in in vitro decreased levels of reduced glutathione (GSH), methionine and cysteine, in a similar way to the decreases we observed in autism plasma. Impaired mitochondrial fatty acid oxidation, elevated plasma VLCFAs, and glutamate toxicity as putative causal factors in the biochemistry, neuropathology, and gender bias in autism are discussed.
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Affiliation(s)
- Elodie Pastural
- Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8
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Abstract
Most of the studies indicate that there is as yet no complete cure for X-ALD. However, methods of the treatment seem to slow rather than treat the disease. One method is the use of Lorenzo's oil in conjunction with a low fat diet, which may help in cerebral X-ALD. X-ALD is in very close resemblance to another neurodegenerative disease, amyotrophic lateral sclerosis (ALS). One of the believed pathomechanisms of ALS is oxidative stress; therefore, this article's emphasis on the role of reactive oxygen species in X-ALD. The aim of the present study was to review the literature concerning the advances in the treatment of X-adrenoleukodystrophy (X-ALD, OMIM # 300100) in the last two decades and to shed more light on the link between oxidative stress and X-ALD. This review article may point to a deficit in reactive oxygen species (ROS) scavenging and/or ROS overproduction being involved in the aetiopathology of these neurodegenerative diseases. Consequently, one of the useful neuronal rescue strategies could be the treatment with antioxidant agents.
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Affiliation(s)
- Mohamed A Al-Omar
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
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