Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy
Huntington’s disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of neurodegeneration in patients with HD remains unclear. In this study we examined striatal medium spiny neurons (MSNs) directly reprogrammed fr...
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Published in | Nature neuroscience Vol. 25; no. 11; pp. 1420 - 1433 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.11.2022
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Huntington’s disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of neurodegeneration in patients with HD remains unclear. In this study we examined striatal medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of patients with HD to model the age-dependent onset of pathology. We found that pronounced neuronal death occurred selectively in reprogrammed MSNs from symptomatic patients with HD (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and control MSNs from age-matched healthy individuals. We observed age-associated alterations in chromatin accessibility between HD-MSNs and pre-HD-MSNs and identified miR-29b-3p, whose age-associated upregulation promotes HD-MSN degeneration by impairing autophagic function through human-specific targeting of the STAT3 3′ untranslated region. Reducing miR-29b-3p or chemically promoting autophagy increased the resilience of HD-MSNs against neurodegeneration. Our results demonstrate miRNA upregulation with aging in HD as a detrimental process driving MSN degeneration and potential approaches for enhancing autophagy and resilience of HD-MSNs.
Oh et al. modeled age-dependent onset of Huntington’s disease by comparing reprogrammed neurons from pre-symptomatic and symptomatic patients. They found that an age-associated miRNA led to autophagy impairment and neurodegeneration. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Y.M.O. and A.S.Y. conceived and developed the idea, designed the experiments, and analyzed data. Y.M.O. performed all experiments, and associated assays and analyses. Y.M.O. and S.W.L. performed neuronal reprogramming throughout figures shown in the study. S.W.L. performed western blot and immunostaining for p62. Y.M.O. and W.K.K. performed ATAC-seq analysis. Y.M.O. and S.C. performed SYTOX assay of G2 analog. T.L. and B.Z. performed WGCNA. V.A.C and S.D. provided the RNAs of human brain samples. K.C. performed LGE analysis. R.E.D., S.C.P., G.A.S., and D.H.P. developed the G2 analog. Y.M.O. and A.S.Y. wrote the manuscript. A.S.Y. supervised the overall project. |
ISSN: | 1097-6256 1546-1726 |
DOI: | 10.1038/s41593-022-01185-4 |