Age-related Huntington's disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy (Figure 2 and S2)

Direct neuronal conversion of fibroblasts from Huntington's disease (HD) patients to striatal medium spiny neurons (MSNs) has been shown to recapitulate neurodegenerative pathology of HD. Here, we carried out comparative analyses between reprogrammed MSNs from patients at different disease stages to investigate age-associated molecular processes driving neurodegeneration. We found that neuronal death was manifested in reprogrammed MSNs from symptomatic HD patients (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and healthy controls. Dissecting the differential cellular state between HD-MSNs and pre-HD-MSNs by transcriptome and chromatin accessibility analyses identified miR-29b-3p, whose age-associated upregulation impairs autophagic function via human-specific targeting of STAT3. Reducing miR-29b-3p or treating with G2-115, a glibenclamide analog, increased the resilience of HD-MSNs against neurodegeneration by promoting autophagy, demonstrating that the autophagic decline during aging in HD underlies MSN degeneration and pointing to potential approaches for enhancing autophagy and resilience of MSNs against degeneration in HD. Overall design: To delineate cellular events underlying HD-MSN degeneration, we compared the transcriptomes of pre-HD-MSNs (six independent patients), HD-MSNs (six independent patients), young-Ctrl-MSNs (six independent samples), and old-Ctrl-MSNs (six independent samples) by RNA-seq (all with triple biological replicates, 72 samples total).