Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin
Rona K Graham1, Yu Deng, Elizabeth J Slow
1Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Insights
Huntington's disease (HD) involves huntingtin (htt) protein cleavage. Blocking caspase-6 cleavage of mutant htt in mice prevents neuronal dysfunction and neurodegeneration, suggesting a key role for this process in HD pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Cleavage of huntingtin (htt) is observed in vitro, with fragments accumulating in Huntington's disease (HD) brains.
- The precise role of htt proteolysis in HD pathogenesis remains unclear.
Purpose of the Study:
- To investigate if caspase cleavage of htt is a critical factor in neuronal dysfunction and neurodegeneration in HD.
- To determine the specific role of caspase-6 in htt cleavage and its contribution to HD pathology.
Main Methods:
- Generation of YAC mice expressing caspase-3 and caspase-6 resistant mutant htt.
- Assessment of neuronal function and striatal neurodegeneration in these mouse models.
- Evaluation of neuroprotection against various stressors (NMDA, QA, staurosporine).
Main Results:
- Mice with mutant htt resistant to caspase-6, but not caspase-3, showed normal neuronal function.
- These caspase-6 resistant mice did not develop striatal neurodegeneration.
- Caspase-6 resistant mutant htt mice were protected from NMDA-, QA-, and staurosporine-induced neurotoxicity.
Conclusions:
- Proteolysis of htt at the caspase-6 site is a significant event in mediating neuronal dysfunction and neurodegeneration in HD.
- Targeting htt proteolysis, specifically at the caspase-6 cleavage site, may offer therapeutic strategies for HD.
- Excitotoxicity and htt proteolysis are highlighted as crucial factors in HD pathogenesis.
Abstract:
Cleavage of huntingtin (htt) has been characterized in vitro, and accumulation of caspase cleavage fragments represents an early pathological change in brains of Huntington's disease (HD) patients. However, the relationship between htt proteolysis and the pathogenesis of HD is unknown. To determine whether caspase cleavage of htt is a key event in the neuronal dysfunction and selective neurodegeneration in HD, we generated YAC mice expressing caspase-3- and caspase-6-resistant mutant htt. Mice expressing mutant htt, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration. Furthermore, caspase-6-resistant mutant htt mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid (QA), and staurosporine. These results are consistent with proteolysis of htt at the caspase-6 cleavage site being an important event in mediating neuronal dysfunction and neurodegeneration and highlight the significant role of htt proteolysis and excitotoxicity in HD.
