Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice
Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia and belongs to the family of nine diseases caused by a polyglutamine expansion in the disease-causing protein. In SCA3, a polyglutamine expansion in ATXN3 causes neuron loss in disease-vulnerable brain regions, resul...
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Elsevier
2025-03-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000439 |
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| author | Alexandra F. Putka Varshasnata Mohanty Stephanie M. Cologna Hayley S. McLoughlin |
| author_facet | Alexandra F. Putka Varshasnata Mohanty Stephanie M. Cologna Hayley S. McLoughlin |
| author_sort | Alexandra F. Putka |
| collection | DOAJ |
| description | Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia and belongs to the family of nine diseases caused by a polyglutamine expansion in the disease-causing protein. In SCA3, a polyglutamine expansion in ATXN3 causes neuron loss in disease-vulnerable brain regions, resulting in progressive loss of coordination and ultimately death. There are no disease-modifying or preventative treatments for this uniformly fatal disorder. Recent studies demonstrate prominent white matter atrophy and microstructural alterations in disease-vulnerable brain regions of SCA3 patients and mouse models. However, the major constituent of white matter – lipids – remains understudied in SCA3.In this study, we conducted the first unbiased investigation of brain lipids in SCA3, focusing on the disease-vulnerable cerebellum of SCA3 postmortem patients and mouse models. Liquid chromatography-mass spectrometry uncovered widespread lipid reductions in patients with SCA3. Lipid downregulation was recapitulated in early- to mid-stage mouse models of SCA3, including transgenic YACQ84 and Knock-in Q300 mice. End-stage Knock-in Q300 mice displayed a progressive reduction in lipid content, highlighting targets that could benefit from early therapeutic intervention. In contrast, Atxn3-Knock-out mice showed mild lipid upregulation, emphasizing a toxic gain-of-function mechanism underlying lipid downregulation in SCA3.We conclude that lipids are significantly altered in SCA3 and establish a platform for continued exploration of lipids in disease through interactive data visualization websites. Pronounced reductions in myelin-enriched lipids suggest that lipid dysregulation could underlie white matter atrophy in SCA3. This study establishes the basis for future work elucidating the mechanistic, biomarker, and therapeutic potential of lipids in SCA3. |
| format | Article |
| id | doaj-art-b7b93c3de44f4840abf49703c6ea4d20 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-b7b93c3de44f4840abf49703c6ea4d202025-02-07T04:46:52ZengElsevierNeurobiology of Disease1095-953X2025-03-01206106827Cerebellar lipid dysregulation in SCA3: A comparative study in patients and miceAlexandra F. Putka0Varshasnata Mohanty1Stephanie M. Cologna2Hayley S. McLoughlin3Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USADepartment of Chemistry, University of Illinois Chicago, Chicago, IL 60607, USADepartment of Chemistry, University of Illinois Chicago, Chicago, IL 60607, USA; Laboratory of Integrated Neuroscience, University of Illinois Chicago, Chicago, IL 60607, USA; Correspondence to: S. Cologna, 5414 Science and Engineering South, 845 West Taylor Street, Chicago, IL 60607, USA.Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Correspondence to: H. McLoughlin, 4013 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia and belongs to the family of nine diseases caused by a polyglutamine expansion in the disease-causing protein. In SCA3, a polyglutamine expansion in ATXN3 causes neuron loss in disease-vulnerable brain regions, resulting in progressive loss of coordination and ultimately death. There are no disease-modifying or preventative treatments for this uniformly fatal disorder. Recent studies demonstrate prominent white matter atrophy and microstructural alterations in disease-vulnerable brain regions of SCA3 patients and mouse models. However, the major constituent of white matter – lipids – remains understudied in SCA3.In this study, we conducted the first unbiased investigation of brain lipids in SCA3, focusing on the disease-vulnerable cerebellum of SCA3 postmortem patients and mouse models. Liquid chromatography-mass spectrometry uncovered widespread lipid reductions in patients with SCA3. Lipid downregulation was recapitulated in early- to mid-stage mouse models of SCA3, including transgenic YACQ84 and Knock-in Q300 mice. End-stage Knock-in Q300 mice displayed a progressive reduction in lipid content, highlighting targets that could benefit from early therapeutic intervention. In contrast, Atxn3-Knock-out mice showed mild lipid upregulation, emphasizing a toxic gain-of-function mechanism underlying lipid downregulation in SCA3.We conclude that lipids are significantly altered in SCA3 and establish a platform for continued exploration of lipids in disease through interactive data visualization websites. Pronounced reductions in myelin-enriched lipids suggest that lipid dysregulation could underlie white matter atrophy in SCA3. This study establishes the basis for future work elucidating the mechanistic, biomarker, and therapeutic potential of lipids in SCA3.http://www.sciencedirect.com/science/article/pii/S0969996125000439LipidomicsNeurodegenerative diseaseOligodendrocyteCholesterolSulfatideMolecular mechanism |
| spellingShingle | Alexandra F. Putka Varshasnata Mohanty Stephanie M. Cologna Hayley S. McLoughlin Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice Neurobiology of Disease Lipidomics Neurodegenerative disease Oligodendrocyte Cholesterol Sulfatide Molecular mechanism |
| title | Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice |
| title_full | Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice |
| title_fullStr | Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice |
| title_full_unstemmed | Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice |
| title_short | Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice |
| title_sort | cerebellar lipid dysregulation in sca3 a comparative study in patients and mice |
| topic | Lipidomics Neurodegenerative disease Oligodendrocyte Cholesterol Sulfatide Molecular mechanism |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000439 |
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