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Cited by 246Genetic Neurodegenerative DiseasesPluripotent Stem Cells ResearchLysosomal Storage Disorders Research

Striatal neurons directly converted from Huntington’s disease patient fibroblasts recapitulate age-associated disease phenotypes

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Victor, Matheus B., Richner, Michelle, Olsen, Hannah E., Lee, Seong Won, Monteys, Alejandro M., Ma, Chunyu, Huh, Christine J., Zhang, Bo +3 more·2018·Nature Neuroscience
DOI 10.1038/s41593-018-0075-7PMC PMC5857213
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Abstract

In Huntington's disease (HD), expansion of CAG codons in the huntingtin gene (HTT) leads to the aberrant formation of protein aggregates and the differential degeneration of striatal medium spiny neurons (MSNs). Modeling HD using patient-specific MSNs has been challenging, as neurons differentiated from induced pluripotent stem cells are free of aggregates and lack an overt cell death phenotype. Here we generated MSNs from HD patient fibroblasts through microRNA-based direct neuronal conversion, bypassing the induction of pluripotency and retaining age signatures of the original fibroblasts. We found that patient MSNs consistently exhibited mutant HTT (mHTT) aggregates, mHTT-dependent DNA damage, mitochondrial dysfunction and spontaneous degeneration in culture over time. We further provide evidence that erasure of age stored in starting fibroblasts or neuronal conversion of presymptomatic HD patient fibroblasts results in differential manifestation of cellular phenotypes associated with HD, highlighting the importance of age in modeling late-onset neurological disorders.

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  • This miRNA-induced neuronal state can synergize with additional transcription factors to generate disease-relevant neuronal subtypes that recapitulate age-dependent neuropathology, including primary tauopathy and adult-onset neurodegeneration of Huntington's disease.

    “This miRNA-induced neuronal state can synergize with additional transcription factors (TFs) to generate disease-relevant neuronal subtypes that recapitulate age-dependent neuropathology (26, 28, 30, 31), including primary tauopathy and adult-onset neurodegeneration of Huntington’s disease (20, 32, 33).”

    From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [33]

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References 49 · Cited by 246

Research works printed but not linked: 37

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Authors
Victor, M. B., Richner, M., Olsen, H. E., Lee, S. W., Monteys, A. M., Ma, C., Huh, C. J., Zhang, B., Davidson, B. L., Yang, X. W., & Yoo, A. S.
Affiliations
  • Washington University in St. Louis (US)
  • Children's Hospital of Philadelphia (US)
  • University of California, Los Angeles (US)
Corresponding author
Yoo, Andrew S.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2018-02-05
Volume
21
Issue
3
Pages
341-352
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-018-0075-7
PMC
PMC5857213
OpenAlex
W2790780682
Cited by
246
References
49
Citations by year
2026: 16 · 2025: 28 · 2024: 34 · 2023: 22 · 2022: 33 · 2021: 33 · 2020: 30 · 2019: 24 · 2018: 26
FWCI
12.87
Type
journal article
Language
en
Update notices
correction (2020-09-02)
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Nature
  • National Institutes of Health (UL1TR002345)
  • Center for Cellular Imaging, Washington University
  • National Institute on Aging (RF1AG056296, R36AG053444)
  • National Institute on Drug Abuse (R25DA027995)
  • National Institute of Neurological Disorders and Stroke (DP2NS083372)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
Huntington's disease, microRNA, patient fibroblasts, medium spiny neurons, striatum, mutant huntingtin aggregates, DNA damage, mitochondrial dysfunction, disease modeling
MeSH terms
Huntingtin Protein, Aging, DNA Damage, Fibroblasts, Humans, Huntington Disease, Neurons, Phenotype, Neostriatum, Oxidative Stress, Neurodegenerative Diseases, Excitatory Postsynaptic Potentials, Gene Expression Profiling, Mitochondrial Diseases, MicroRNAs, Pluripotent Stem Cells

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