Funded in part by Teva Pharmaceutical Industries
Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease
Ehrnhoefer DE, Martin DDO, Schmidt ME, Qiu X, Ladha S, Caron NS, Skotte NH, Nguyen YTN, Vaid K, Southwell AL, Engemann S, Franciosi S, Hayden MR
Acta neuropathologica communications · 69 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- Animals
- Main outcome
- Mechanisms only
Who paid for it
- Funding
- Industry funded
- Company
- Teva Pharmaceutical Industries
- Government
- Government of Canada
- Government
- Michael Smith Health Research BC
- Government
- National Science Council
- University or hospital
- University of British Columbia
- Government
- Canadian Institutes of Health Research
- Government
- CIHR
- Nonprofit
- Michael Smith Foundation for Health Research
- Authors
- At least one author declares a financial tie to industry
- Grants
- Canadian Institutes of Health Research (20R90174); Canadian Institutes of Health Research (CIHR 20R90174)
Based on 8 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2018-02-26 · Acta Neuropathol Commun · vol. 6 · issue 1 · p. 16
- Publisher
- Springer Science+Business Media
- Cited
- 82 citations · more than 92% of similar papers · 2.9× the field average
- Impact
- Top 10% most cited in its field
- References
- 66 works
- Access
- Open access (journal) · CC-BY
- Research areas
- Genetic Neurodegenerative Diseases · Autophagy in Disease and Therapy · Mitochondrial Function and Pathology
- Keywords
- Huntingtin, Autophagy, Cell biology, Proteolysis, Biology, Huntingtin Protein, Huntington's disease, Neuroprotection, Mutant, Genetics, Biochemistry, Enzyme, Neuroscience, Disease, Apoptosis, Medicine, Internal medicine, Gene
- MeSH
- liver, cerebral cortex, neurons, cells, cultured, cos cells, animals, mice, transgenic, humans, huntington disease, disease models, animal, fasting, random allocation, aging, mutation, autophagy, female, male, proteolysis, huntingtin protein, chlorocebus aethiops
13 authors
From CA, DE
- Dagmar E. Ehrnhoefer · correspondingUniversity of British Columbia; BioMed X Institute
- Dale D. O. MartinUniversity of British Columbia
- Mandi E. SchmidtUniversity of British Columbia
- Xiaofan QiuUniversity of British Columbia
- Safia LadhaUniversity of British Columbia
- Nicholas S. CaronUniversity of British Columbia
Abstract
Huntington disease (HD) is caused by the expression of mutant huntingtin (mHTT) bearing a polyglutamine expansion. In HD, mHTT accumulation is accompanied by a dysfunction in basal autophagy, which manifests as specific defects in cargo loading during selective autophagy. Here we show that the expression of mHTT resistant to proteolysis at the caspase cleavage site D586 (C6R mHTT) increases autophagy, which may be due to its increased binding to the autophagy adapter p62. This is accompanied by faster degradation of C6R mHTT in vitro and a lack of mHTT accumulation the C6R mouse model with age. These findings may explain the previously observed neuroprotective properties of C6R mHTT. As the C6R mutation cannot be easily translated into a therapeutic approach, we show that a scheduled feeding paradigm is sufficient to lower mHTT levels in YAC128 mice expressing cleavable mHTT. This is consistent with a previous model, where the presence of cleavable mHTT impairs basal autophagy, while fasting-induced autophagy remains functional. In HD, mHTT clearance and autophagy may become increasingly impaired as a function of age and disease stage, because of gradually increased activity of mHTT-processing enzymes. Our findings imply that mHTT clearance could be enhanced by a regulated dietary schedule that promotes autophagy.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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