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 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.
Authors
- Kin Ming Kwan (ORCID: https://orcid.org/0000-0002-1246-2398)
- Kevin Talbot (ORCID: https://orcid.org/0000-0001-5490-1697)
- Lok I Leong
- Maurice A. Curtis (ORCID: https://orcid.org/0000-0003-4496-0233)
- Zhefan Stephen Chen (ORCID: https://orcid.org/0000-0002-9276-0378)
- Clinton P. Turner (ORCID: https://orcid.org/0000-0002-2138-7633)
- Lynette J. Tippett (ORCID: https://orcid.org/0000-0003-4592-6600)
- Jacquelyne Ka‐Li Sun (ORCID: https://orcid.org/0000-0001-6975-1644)
- Christopher E. Pearson (ORCID: https://orcid.org/0000-0001-9545-4205)
- Xiao Lin (ORCID: https://orcid.org/0000-0002-2559-2343)
- Hei‐Man Chow (ORCID: https://orcid.org/0000-0003-1203-2096)
- Shaohong Peng (ORCID: https://orcid.org/0000-0002-9249-4727)
- Alex Chun Koon (ORCID: https://orcid.org/0000-0002-4274-7052)
- Terence Gall-Duncan (ORCID: https://orcid.org/0000-0002-7314-7658)
- Ting‐Fung Chan (ORCID: https://orcid.org/0000-0002-0489-3884)
- Ho Yin Edwin Chan (ORCID: https://orcid.org/0000-0003-4307-474X)
- Richard L. M. Faull (ORCID: https://orcid.org/0000-0003-3385-9498)
- Yuming Wei (ORCID: https://orcid.org/0000-0003-2622-382X)
- Tsz Ho Li (ORCID: https://orcid.org/0000-0002-2699-3616)
- Junzhe Huang (ORCID: https://orcid.org/0000-0003-4859-9385)
- Ho Ko (ORCID: https://orcid.org/0000-0002-0254-3274)
- N Wong
Institutions
- University of Auckland (NZ)
- Chinese University of Hong Kong (HK)
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Auckland City Hospital (NZ)
- John Radcliffe Hospital (GB)
- Structural Genomics Consortium (CA)
- University of Oxford (GB)
- Hong Kong Biotechnology Organization (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1038/s41467-025-58618-4
- Citations
- 5
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 4.55
Funders
- Research Grants Council, University Grants Committee
- Innovation and Technology Commission
- Chinese University of Hong Kong
- State Key Laboratory for Agrobiotechnology