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

Zhefan Stephen Chen, Shaohong Isaac Peng, Lok I Leong, Terence Gall-Duncan, Nathan Siu Jun Wong, Tsz Ho Li, Xiao Lin, Yuming Wei, Alex Chun Koon, Junzhe Huang, Jacquelyne Ka-Li Sun, Clinton Turner, Lynette Tippett, Maurice A. Curtis, Richard L. M. Faull, Kin Ming Kwan, Hei-Man Chow, Ho Ko, Ting-Fung Chan, Kevin Talbot, Christopher E. Pearson and Ho Yin Edwin Chan ()
Additional contact information
Zhefan Stephen Chen: The Chinese University of Hong Kong
Shaohong Isaac Peng: The Chinese University of Hong Kong
Lok I Leong: The Chinese University of Hong Kong
Terence Gall-Duncan: The Hospital for Sick Children
Nathan Siu Jun Wong: The Chinese University of Hong Kong
Tsz Ho Li: The Chinese University of Hong Kong
Xiao Lin: The Chinese University of Hong Kong
Yuming Wei: The Chinese University of Hong Kong
Alex Chun Koon: The Chinese University of Hong Kong
Junzhe Huang: The Chinese University of Hong Kong
Jacquelyne Ka-Li Sun: The Chinese University of Hong Kong
Clinton Turner: Auckland City Hospital
Lynette Tippett: University of Auckland
Maurice A. Curtis: University of Auckland
Richard L. M. Faull: University of Auckland
Kin Ming Kwan: The Chinese University of Hong Kong
Hei-Man Chow: The Chinese University of Hong Kong
Ho Ko: The Chinese University of Hong Kong
Ting-Fung Chan: The Chinese University of Hong Kong
Kevin Talbot: University of Oxford
Christopher E. Pearson: The Hospital for Sick Children
Ho Yin Edwin Chan: The Chinese University of Hong Kong

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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 demonstrate that the Yin Yang 1 protein, a transcriptional repressor of PAPD5, is recruited to both RNA foci and protein aggregates, resulting in an upregulation of PAPD5 expression in Huntington’s disease (HD). Additionally, we identify a subset of PAPD5-regulated miRNAs with increased adenylation and reduced expression in our disease model. We focus on miR-7-5p and find that its reduction causes the activation of the TAB2-mediated TAK1–MKK4–JNK pro-apoptotic pathway. This pathway is also activated in induced pluripotent stem cell-derived striatal neurons and post-mortem striatal tissues isolated from HD patients. In addition, we discover that a small molecule PAPD5 inhibitor, BCH001, can 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.

Date: 2025
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DOI: 10.1038/s41467-025-58618-4

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