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Updated: May 15, 2025
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5
Zhefan Stephen Chen1,2, Shaohong Isaac Peng1, Lok I Leong1
1School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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.
Insights
Huntington's disease involves dysfunctional microRNAs (miRNAs). Researchers found that inhibiting Poly(A) RNA polymerase D5 (PAPD5) reduces cell death and neurodegeneration, offering a potential therapeutic strategy.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression.
- Poly(A) RNA polymerase D5 (PAPD5) modifies miRNA 3' ends.
- Dysregulation of these processes is implicated in neurodegenerative diseases.
Purpose of the Study:
- To investigate the role of PAPD5 and Yin Yang 1 (YY1) in Huntington's disease (HD).
- To identify specific miRNA alterations in HD.
- To explore PAPD5 inhibition as a therapeutic strategy for HD.
Main Methods:
- Analysis of YY1 recruitment to RNA and protein aggregates.
- Measurement of PAPD5 expression and miRNA adenylation.
- Investigating the miR-7-5p/TAK1 pathway activation in HD models.
- Testing a PAPD5 inhibitor (BCH001) in disease models.
Main Results:
- YY1 represses PAPD5, but its aggregation leads to increased PAPD5 expression in HD.
- Specific miRNAs show altered adenylation and reduced expression in HD.
- Reduced miR-7-5p activates a pro-apoptotic pathway (TAK1-MKK4-JNK).
- BCH001 treatment ameliorates cell death and neurodegeneration in HD models.
Conclusions:
- PAPD5-mediated miRNA dysfunction is crucial in HD pathogenesis.
- Targeting PAPD5 offers a promising therapeutic avenue for Huntington's disease.
- The study elucidates a novel molecular mechanism contributing to HD progression.
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