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Expanded ATXN1 alters transcription and calcium signaling in SCA1 human motor neurons differentiated from induced pluripotent stem cells.
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- Additional Information
- Source:
Publisher: Academic Press Country of Publication: United States NLM ID: 9500169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-953X (Electronic) Linking ISSN: 09699961 NLM ISO Abbreviation: Neurobiol Dis Subsets: MEDLINE
- Publication Information:
Publication: San Diego, CA : Academic Press
Original Publication: Oxford : Blackwell Science, c1994-
- Subject Terms:
- Abstract:
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited and lethal neurodegenerative disease caused by the abnormal expansion of CAG repeats in the ATAXIN-1 (ATXN1) gene. Pathological studies identified dysfunction and loss of motor neurons (MNs) in the brain stem and spinal cord, which are thought to contribute to premature lethality by affecting the swallowing and breathing of SCA1 patients. However, the molecular and cellular mechanisms of MN pathogenesis remain unknown. To study SCA1 pathogenesis in human MNs, we differentiated induced pluripotent stem cells (iPSCs) derived from SCA1 patients and their unaffected siblings into MNs. We examined proliferation of progenitor cells, neurite outgrowth, spontaneous and glutamate-induced calcium activity of SCA1 MNs to investigate cellular mechanisms of pathogenesis. RNA sequencing was then used to identify transcriptional alterations in iPSC-derived MN progenitors (pMNs) and MNs which could underlie functional changes in SCA1 MNs. We found significantly decreased spontaneous and evoked calcium activity and identified dysregulation of genes regulating calcium signaling in SCA1 MNs. These results indicate that expanded ATXN1 causes dysfunctional calcium signaling in human MNs.
Competing Interests: Declaration of competing interest The authors declare no competing financial interests.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- Grant Information:
R01 NS107387 United States NS NINDS NIH HHS; R01 NS109077 United States NS NINDS NIH HHS
- Contributed Indexing:
Keywords: Calcium signaling; Motor neurons; SCA1; Transcription; iPSCs
- Accession Number:
0 (Ataxin-1)
0 (ATXN1 protein, human)
- Publication Date:
Date Created: 20240922 Date Completed: 20241020 Latest Revision: 20241029
- Publication Date:
20241029
- Accession Number:
PMC11514977
- Accession Number:
10.1016/j.nbd.2024.106673
- Accession Number:
39307401
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