Striatal neuronal models of Huntington's disease via direct conversion: Modeling age-dependent disease phenotypes

MicroRNAs (miRNAs), miR-9/9∗ and miR-124 (miR-9/9∗-124), orchestrate direct conversion of human fibroblasts into neurons via its neurogenic and cell-fate conversion (reprogramming) activities. Under miR-9/9∗-124-mediated neuronal reprogramming, striatum-enriched transcription factors define the subtype-specific neuronal identity of medium spiny neurons (MSNs), the major cell type degenerated in Huntington's disease (HD). Furthermore, MSNs generated from HD patient–derived fibroblasts (HD-MSNs) recapitulate HD-associated phenotypes and neurodegeneration resulting from the age-associated decline in critical cellular functions such as autophagy. In this review, we provide an overview of miRNAs as cellular reprogramming effectors and the synergism of miRNA-induced neuronal state with striatum-enriched transcription factors to generate MSNs. Moreover, we describe the utility of reprogrammed HD-MSNs in modeling adult-onset neuropathology of HD. Finally, we provide insights into age-associated cell-intrinsic changes contributing to the onset of neurodegeneration detected in HD-MSNs.