Modeling Huntington disease through microRNA-mediated neuronal reprogramming identifies age-associated autophagy dysfunction driving the onset of neurodegeneration

Young Mi Oh, Seong Won Lee, Andrew S. Yoo

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Huntington disease (HD) is an inherited neurodegenerative disease with adult-onset clinical symptoms. However, the mechanism by which aging triggers the onset of neurodegeneration in HD patients remains unclear. Modeling the age-dependent progression of HD with striatal medium spiny neurons (MSNs) generated by direct reprogramming of fibroblasts from HD patients at different disease stages identifies age-dependent decline in critical cellular functions such as autophagy/macroautophagy and onset of neurodegeneration. Mechanistically, MSNs derived from symptomatic HD patients (HD-MSNs) are characterized by increased chromatin accessibility proximal to the MIR29B-3p host gene and its upregulation compared to MSNs from younger pre-symptomatic patients. MIR29B-3p in turn targets and represses STAT3 (signal transducer and activator of transcription 3) that controls the biogenesis of autophagosomes, leading to HD-MSN degeneration. Our recent study demonstrates age-associated microRNA (miRNA) and autophagy dysregulation linked to MSN degeneration, and potential approaches for protecting MSNs by enhancing autophagy in HD. Abbreviations: HD: Huntington disease; mHTT: mutant HTT; MIR9/9*-124: MIR9/9* and MIR124; miRNA: microRNA; MSN: medium spiny neuron; STAT3: signal transducer and activator of transcription 3.

Original languageEnglish
Pages (from-to)2613-2615
Number of pages3
JournalAutophagy
Volume19
Issue number9
DOIs
StatePublished - 2023

Keywords

  • Aging
  • Huntington disease
  • autophagy/macroautophagy
  • microRNA-mediated neuronal reprogramming
  • neurodegeneration

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