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

MicroRNAs (miRNAs) are small non-coding RNAs that play crucial roles in post-transcriptional gene regulation. Poly(A) RNA polymerase D5 (PAPD5) catalyzes the addition of adenosine to the 3′ end of miRNAs. In this study, we demonstrated that the Yin Yang 1 protein, a transcriptional repressor of PAPD5, was recruited to both RNA foci and protein aggregates, resulting in an upregulation of PAPD5 expression in Huntington’s disease (HD). Additionally, we identified a subset of PAPD5-regulated miRNAs with increased adenylation and reduced expression in our disease model. We focused on miR-7-5p and found that its reduction caused the activation of the TAB2-mediated TAK1–MKK4–JNK pro-apoptotic pathway. This pathway was also activated in induced pluripotent stem cell-derived striatal neurons and post-mortem striatal tissues isolated from HD patients. In addition, we discovered that a small molecule PAPD5 inhibitor, BCH001, could mitigate cell death and neurodegeneration in our disease models. This study highlights the importance of PAPD5-mediated miRNA dysfunction in HD pathogenesis and suggests a potential therapeutic direction for the disease. We performed small RNA-seq to investigate the 3’ adenylation levels of the miRNAs in SK-N-MC cells overexpressed with either the wild-type PAPD5 protein or a catalytic-inactive PAPD5 mutant (PAPD5 D256A & D258A).