Age-related Huntington's Disease Progression Modeled in Directly Reprogrammed Patient-derived Striatal Neurons Highlights Impaired Autophagy

Overview

Journal Nat Neurosci

Date 2022 Oct 27

PMID 36303071

Authors

Young Mi Oh

Seong Won Lee

Woo Kyung Kim

Shawei Chen

Victoria A Church

Kitra Cates

Tiandao Li

Bo Zhang

Roland E Dolle

Sonika Dahiya

Stephen C Pak

Gary A Silverman

David H Perlmutter

Andrew S Yoo

Affiliations

Soon will be listed here.

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.

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