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 inNature neuroscience Vol. 25; no. 11; pp. 1420 - 1433
Main Authors Oh, Young Mi, Lee, Seong Won, Kim, Woo Kyung, Chen, Shawei, Church, Victoria A., Cates, Kitra, Li, Tiandao, Zhang, Bo, Dolle, Roland E., Dahiya, Sonika, Pak, Stephen C., Silverman, Gary A., Perlmutter, David H., Yoo, Andrew S.
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.11.2022
Nature Publishing Group
Subjects
3' Untranslated regions
631/378/1689/1558
631/378/1689/364
631/378/2611
631/80/39
Age
Aging
Animal Genetics and Genomics
Animals
Autophagy
Behavioral Sciences
Biological Techniques
Biomedical and Life Sciences
Biomedicine
Chromatin
Corpus Striatum - physiology
Degeneration
Disease Models, Animal
Disease Progression
Fibroblasts
Humans
Huntington Disease - pathology
Huntington's disease
Huntingtons disease
MicroRNAs - genetics
miRNA
Neostriatum
Neurobiology
Neurodegeneration
Neurodegenerative diseases
Neurons
Neurons - physiology
Neurosciences
Patients
Resilience
Signs and symptoms
Spiny neurons
Stat3 protein
Online AccessGet full text
ISSN1097-6256
1546-1726
1546-1726
DOI10.1038/s41593-022-01185-4

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Abstract 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.
AbstractList 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.
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.
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.
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 HD patients remains unclear. Here, we examined striatal medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of HD patients to model the age-dependent onset of pathology. We found that pronounced neuronal death occurred selectively in reprogrammed MSNs from symptomatic HD patients (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 STAT3 3’UTR. 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.
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.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.
Author Lee, Seong Won
Perlmutter, David H.
Yoo, Andrew S.
Dolle, Roland E.
Pak, Stephen C.
Kim, Woo Kyung
Church, Victoria A.
Li, Tiandao
Silverman, Gary A.
Zhang, Bo
Oh, Young Mi
Chen, Shawei
Cates, Kitra
Dahiya, Sonika
AuthorAffiliation 1 Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
3 Department of Biochemistry, Washington University School of Medicine, St. Louis, MO 63110, USA
2 Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
4 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
6 These authors contributed equally
5 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/36303071$$D View this record in MEDLINE/PubMed
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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.
ORCID 0000-0001-8981-5537
0000-0002-5585-0964
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0000-0002-2686-2843
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Snippet Huntington’s disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of...
Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of...
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pubmed
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springer
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StartPage 1420
SubjectTerms 3' Untranslated regions
631/378/1689/1558
631/378/1689/364
631/378/2611
631/80/39
Age
Aging
Animal Genetics and Genomics
Animals
Autophagy
Behavioral Sciences
Biological Techniques
Biomedical and Life Sciences
Biomedicine
Chromatin
Corpus Striatum - physiology
Degeneration
Disease Models, Animal
Disease Progression
Fibroblasts
Humans
Huntington Disease - pathology
Huntington's disease
Huntingtons disease
MicroRNAs - genetics
miRNA
Neostriatum
Neurobiology
Neurodegeneration
Neurodegenerative diseases
Neurons
Neurons - physiology
Neurosciences
Patients
Resilience
Signs and symptoms
Spiny neurons
Stat3 protein
Title Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy
URI https://link.springer.com/article/10.1038/s41593-022-01185-4
https://www.ncbi.nlm.nih.gov/pubmed/36303071
https://www.proquest.com/docview/2731320057
https://www.proquest.com/docview/2730314588
https://pubmed.ncbi.nlm.nih.gov/PMC10162007
Volume 25
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