Age-dependent alterations in the human striatum identify a PPP1R15B-miR-196a node as a modifier of Huntington’s disease phenotypes

Polyglutamine expansion in Huntingtin (HTT) causes its aggregation and progressive loss of striatal neurons in Huntington’s disease (HD). HD is a mostly adult-onset neurodegenerative disorder with no disease-modifying therapies. Here we found that human striatal aging is associated with a global upregulation of genes involved in translation, including the translation and proteostasis regulator PPP1R15B (R15B). We used the R15B inhibitor Raphin1 to investigate if the age-associated changes could modify HD pathology. R15B inhibition rescued early learning and late motor deficits in HDYAC128 mice. In striatal medium spiny neurons directly reprogrammed from fibroblasts of symptomatic HD patients (HD-MSNs), Raphin1 reduced the formation of mutant HTT aggregates and neuronal death. Genetic knockdown of R15B also protected HD-MSNs from neurodegeneration whereas its overexpression exacerbated disease phenotypes. Moreover, both human striatum and reprogrammed MSNs exhibited age-dependent decline of miR-196a, a microRNA that directly targets non-conserved sites in human R15B 3’UTR and overexpressing miR-196a lowered mutant HTT aggregation. This work identifies age-dependent alterations in miR-196a and its target R15B and demonstrates the therapeutic potential of reversing these changes in diverse models and readouts of HD. We propose miR-196a and R15B as disease-modifying targets in HD.