Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5

Abstract MicroRNAs (miRNAs) are small non-coding RNAs responsible for RNA silencing and the posttranscriptional regulation of gene expression. Poly(A) RNA polymerase D5 (PAPD5) catalyzes the addition of adenosine to the 3′ end of miRNAs, which promotes their subsequent degradation. In this study, we demonstrated that the Yin Yang 1 (YY1) protein, a transcriptional repressor of PAPD5, was recruited to both RNA foci and protein aggregates, which caused the upregulation of PAPD5 expression in Huntington’s disease (HD). We further identified a subset of PAPD5-regulated miRNAs with downregulated levels in our disease model. We focused on miR-504-5p and miR-7-5p and found that their reduction caused the activation of the TAB1/2-mediated TAK1–MKK4–JNK pro-apoptotic pathway. We further showed that this pathway was activated in HD patient induced pluripotent stem cell-derived neurons. In addition, we discovered that a small molecule PAPD5 inhibitor, BCH001, mitigated the cell death and neurodegeneration in our disease models. This study highlights the importance of PAPD5-mediated miRNA dysfunction in the pathogenesis of HD and as a potential therapeutic direction for the disease.