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Recent insights into the molecular pathogenesis of Huntington disease
B R Leavitt1, C L Wellington, M R Hayden
1Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.
Insights
Huntington disease (HD) involves a CAG repeat expansion in the huntingtin (HTT) gene. Inhibiting caspase cleavage of mutant HTT protein fragments may offer a therapeutic strategy for this neurodegenerative disorder.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington disease (HD) is a neurodegenerative disorder characterized by CAG repeat expansion in the huntingtin (HTT) gene.
- This expansion leads to an uninterrupted polyglutamine stretch in the huntingtin protein (htt).
Purpose of the Study:
- To review the clinical, genetic, and neuropathological features of HD.
- To discuss recent insights into HD pathogenesis, focusing on the role of CAG repeat size and htt cleavage.
Main Methods:
- Analysis of a human HD patient database to correlate CAG repeat size with age of onset and penetrance.
- Utilizing a YAC transgenic mouse model to study striatal neurodegeneration and htt cleavage.
- In vitro studies examining htt as a substrate for caspases and the toxicity of N-terminal fragments.
Main Results:
- CAG repeat size is crucial for HD pathogenesis, enabling a predictive model for disease onset.
- Striatal neurodegeneration in a mouse model correlates with htt cleavage and nuclear translocation of N-terminal fragments.
- Caspase cleavage of htt generates a toxic fragment, and inhibiting this process reduces mutant htt toxicity.
Conclusions:
- Cleavage of huntingtin, producing a truncated N-terminal fragment, is a key step in HD pathogenesis.
- Inhibiting this htt cleavage represents a potential therapeutic strategy for Huntington disease.
Abstract:
Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HD gene resulting in expression of an uninterrupted polyglutamine stretch within the N-terminus of its protein product huntingtin (htt). In this article we review the clinical, genetic, and neuropathological features of HD and discuss recent insights into the pathogenesis of HD. Examining the role of CAG repeat size on age of onset and penetrance in HD using a refined database of human HD patients has provided further support for the importance of the CAG repeat in the pathogenesis of HD and information leading to a predictive model for the likelihood of being affected by a specific age for a particular CAG expansion. In a YAC transgenic mouse model that replicates key elements of the HD phenotype, the development of selective striatal neurodegeneration is coincident with cleavage of htt and translocation of the N-terminal htt fragment into the nucleus. We also review in vitro evidence that htt is a substrate for cleavage by a group of cysteine proteases involved in apoptotic death-the caspases, and that caspase cleavage of htt results in the generation of a toxic N-terminal fragment. Inhibiting caspase cleavage of huntingtin eliminates the toxicity of the mutant htt protein. These results suggest that cleavage of huntingtin resulting in production of a truncated N-terminal fragment may be a crucial step in the pathogenesis of Huntington disease and that inhibition of this process may be a potential therapeutic strategy for this currently untreatable disorder.