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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Wild-type C9orf72 drives proteasomal dysfunction and mutant aggregates via a Stat1-Isg15 axis in Huntington's disease
Siew Chin Chan1, Chih-Wei Tung2, Chih-Yi Chang3
1Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
Summary
Wild-type C9orf72 (wt-C9orf72) promotes Huntington's disease (HD) pathology by increasing mutant Huntingtin (mHTT) aggregation. This occurs through a novel C9orf72-Stat1-Isg15 pathway that impairs the ubiquitin-proteasome system (UPS).
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Mutant C9orf72 is a known cause of neurodegenerative diseases like ALS and FTD.
- The role of wild-type C9orf72 (wt-C9orf72) in neurodegeneration, particularly Huntington's disease (HD), is largely unknown.
- Huntington's disease involves mutant Huntingtin (mHTT) aggregation and impaired proteostasis, but upstream causes of UPS dysfunction are unclear.
Purpose of the Study:
- To investigate the role of wt-C9orf72 in regulating mHTT aggregation and proteostasis in HD models.
- To identify the molecular mechanisms linking wt-C9orf72 to HD pathogenesis.
- To explore potential therapeutic targets within the identified pathway.
Main Methods:
- Analysis of public transcriptomic datasets and R6/2 mouse brain lysates for C9orf72 expression.
- Functional analyses of wt-C9orf72 overexpression on mHTT aggregation, apoptosis, and cell viability.
- Unbiased proteomic profiling to identify downstream effectors.
- Genetic suppression of identified effectors (Stat1, Isg15) to assess their role in C9orf72-mediated pathology.
- Validation in R6/2 HD mouse models.
Main Results:
- wt-C9orf72 overexpression exacerbates mHTT aggregation, apoptosis, and reduces cell viability in HD models.
- Stat1 was identified as a key downstream effector, with wt-C9orf72 promoting Stat1 activation and nuclear translocation.
- This leads to Isg15 upregulation, which disrupts the ubiquitin-proteasome system (UPS), causing polyubiquitinated protein accumulation.
- Genetic suppression of Stat1 or Isg15 significantly reduced C9orf72-associated mHTT aggregation.
- Elevated Stat1, p-Stat1, and Isg15 levels were observed in R6/2 HD mouse brains.
Conclusions:
- A novel wt-C9orf72-Stat1-Isg15 signaling axis promotes proteasomal dysfunction and mHTT aggregation.
- This pathway provides new insights into wt-C9orf72's role in protein homeostasis and HD pathogenesis.
- Targeting the C9orf72-Stat1-Isg15 axis may offer therapeutic strategies for Huntington's disease.
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