This week we profile a recent publication in the FASEB Journal from Dr. Dale Martin (pictured) in
the laboratory of Dr. Michael Hayden at the Centre for Molecular Medicine and Therapeutics at UBC.
Can you provide a brief overview of your lab’s current research focus?
The research in the Hayden lab focuses on identifying points of convergence within cellular pathways that lead to the reduction of the mutant protein huntingtin (HTT), the causative agent of Huntington Disease (HD). HD is a devastating neurodegenerative disease caused by an autosomal dominant mutation in the HTT gene, which codes for an expansion in the HTT protein that leads to a toxic gain of function mutation and protein aggregation. The Hayden lab has also shown that the mutation may also lead to a toxic loss of function in its role in regulating autophagy, a pathway important for the clearance of aggregated proteins, like mutant HTT. HTT undergoes a myriad of post-translational modifications that regulate how it functions. Some of these modifications affect the toxicity of the mutant huntingtin as well as its aggregation. In particular, HTT is proteolyzed by a number of proteases, including caspases. These have been shown to play a crucial role in the pathogenesis of the mutant protein and progression of the disease in mouse models, particularly proteolysis by caspase-6, a pro-death enzyme, at amino acid 586. Previously, we have shown that blocking proteolysis at this site completely ameliorates the HD phenotype in mice.
What is the significance of the findings in this publication?
In this study, we identified a novel caspase cleavage site mediated by caspase-1 at amino acid 572. Caspase-1 is typically activated during inflammation. When we blocked proteolysis or cleavage at this site in cell culture, we found that the mutant protein formed significantly less aggregates and that the half-life of the protein significantly decreased, suggesting it is cleared from the cell faster. A caspase-1 inhibitor was shown to decrease not only caspase-1-mediated cleavage of HTT at 572, but at the 586 caspase-6 site as well. This is likely due to the fact that caspase-1 also cleaves and activates caspase-6. Therefore, targeting caspase-1 could be beneficial two-fold; by inhibiting the new site of cleavage at 572 as well as by inhibiting activation of caspase-6 through caspase-1 leading to decreased 586 cleavage.
What are the next steps for this research?
Ultimately, we would like to study the in vivo effects of inhibiting caspase-1 in an HD mouse model. A recent study by Dr. Andrea Leblanc’s group at McGill University showed that a caspase-1 inhibitor was beneficial in an Alzheimer’s disease mouse model. We think caspase-1 inhibition could also be beneficial in HD.
This research was funded by:
This work was supported by the Canadian Institutes of Health Research (CIHR 20R90174). Senior author Dr. Michael Hayden is a Killam Professor and founder of the Centre for Molecular Medicine and Therapeutics (CMMT) at UBC and a Canadian Research Chair in Human Genetics and Molecular Medicine. Lead author Dr. Dale Martin was supported by postdoctoral fellowships from CIHR, the Michael Smith Foundation for Health Research, and the Bluma Tischler Fellowship from UBC and is now an Assistant Professor in the Department of Biology at the University of Waterloo. Co-author Mandi Schmidt was awarded a Vanier Canada Graduate Scholarship from CIHR.
