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Calpain activation in Huntington's disease
Juliette Gafni1, Lisa M Ellerby
1Buck Institute for Age Research, Novato, California 94945, USA.
Summary
Activated calpain protease cleaves huntingtin protein fragments, a key step in Huntington's disease (HD) pathogenesis. This finding implicates calpain in the neurodegenerative process of HD.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder.
- It is caused by a CAG expansion in the huntingtin (Htt) gene.
- Abnormal processing of mutant Htt is critical in HD initiation.
Purpose of the Study:
- To identify the protease responsible for abnormal Htt processing in HD.
- To investigate the role of calpain in Htt cleavage.
Main Methods:
- Detection of activated calpain in human HD caudate tissue.
- Analysis of N-terminal Htt proteolytic fragments in HD tissue.
- In vitro cleavage of Htt by exogenous calpain.
Main Results:
- Activated calpain was detected in human HD tissue, but not in controls.
- A major N-terminal Htt fragment in HD tissue resulted from calpain cleavage.
- Calpain cleavage of Htt is dependent on polyglutamine tract length.
Conclusions:
- Calpain plays a role in the proteolytic processing of Htt in HD.
- Calpain-mediated cleavage of Htt is implicated in the pathogenesis of Huntington's disease.