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

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 host gene and its upregulation compared to MSNs from younger pre-symptomatic patients. 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. HD: Huntington disease; mHTT: mutant HTT; ; miRNA: microRNA; MSN: medium spiny neuron; STAT3: signal transducer and activator of transcription 3.