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

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.

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

Figure 1.

Modeling age-related Huntington disease progression through microRNA-mediated neuronal reprogramming. (A) Experimental scheme of MSNs conversion from fibroblasts of pre-symptomatic (pre-HD-MSNs), symptomatic HD patients (HD-MSNs), and respective healthy control individuals of similar ages (young or old-Ctrl-MSNs). MSNs were reprogrammed by overexpressing MIR9/9* and MIR124 (MIR9/9*-124), and MSN subtype-defining transcription factors, BCL11B/CTIP2, DLX1, DLX2, and MYT1L (CDM). (B) Top: Age-dependent changes in the balance between autophagy activity and neuronal death in patient-derived MSNs. Middle: the sequence of MIR29B-3p seed and seed-match in human STAT3 3′ UTR. Bottom: Aging-induced interaction between MIR29B-3p and STAT3 leading to autophagy impairment and neurodegeneration of HD-MSNs.