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

Autophagy. 2023 Sep;19(9):2613-2615. doi: 10.1080/15548627.2023.2175572. Epub 2023 Feb 8.


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.

Keywords: Aging; Huntington disease; autophagy/macroautophagy; microRNA-mediated neuronal reprogramming; neurodegeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Comment

MeSH terms

  • Animals
  • Autophagy / genetics
  • Corpus Striatum
  • Disease Models, Animal
  • Humans
  • Huntingtin Protein / genetics
  • Huntington Disease* / genetics
  • MicroRNAs* / genetics
  • Neurodegenerative Diseases*
  • STAT3 Transcription Factor


  • STAT3 Transcription Factor
  • MicroRNAs
  • Huntingtin Protein