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Abstract
Caspase-6 (Casp6) is implicated in Alzheimer disease (AD) cognitive impairment and pathology. Hippocampal atrophy is associated with cognitive impairment in AD. Here, a rare functional exonic missense CASP6 single nucleotide polymorphism (SNP), causing the substitution of asparagine with threonine at amino acid 73 in Casp6 (Casp6N73T), was associated with hippocampal subfield CA1 volume preservation. Compared to wild type Casp6 (Casp6WT), recombinant Casp6N73T altered Casp6 proteolysis of natural substrates Lamin A/C and α-Tubulin, but did not alter cleavage of the Ac-VEID-AFC Casp6 peptide substrate. Casp6N73T-transfected HEK293T cells showed elevated Casp6 mRNA levels similar to Casp6WT-transfected cells, but, in contrast to Casp6WT, did not accumulate active Casp6 subunits nor show increased Casp6 enzymatic activity. Electrophysiological and morphological assessments showed that Casp6N73T recombinant protein caused less neurofunctional damage and neurodegeneration in hippocampal CA1 pyramidal neurons than Casp6WT. Lastly, CASP6 mRNA levels were increased in several AD brain regions confirming the implication of Casp6 in AD. These studies suggest that the rare Casp6N73T variant may protect against hippocampal atrophy due to its altered catalysis of natural protein substrates and intracellular instability thus leading to less Casp6-mediated damage to neuronal structure and function.
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1 Lady Davis Institute for Medical Research at Jewish General Hospital, Montréal, Canada (GRID:grid.414980.0) (ISNI:0000 0000 9401 2774); McGill University, Department of Anatomy and Cell Biology, Montréal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
2 Indiana University School of Medicine, Department of Radiology and Imaging Sciences and Indiana Alzheimer’s Disease Research Center, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
3 McGill University, Centre for Research in Neuroscience, the BRaIN Program, Department of Medicine, and Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Centre, Montreal General Hospital, Montréal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
4 Lady Davis Institute for Medical Research at Jewish General Hospital, Montréal, Canada (GRID:grid.414980.0) (ISNI:0000 0000 9401 2774); McGill University, Department of Neurology and Neurosurgery, Montréal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
5 Indiana University School of Medicine, Stark Neurosciences Research Institute, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
6 Lady Davis Institute for Medical Research at Jewish General Hospital, Montréal, Canada (GRID:grid.414980.0) (ISNI:0000 0000 9401 2774); McGill University, Department of Anatomy and Cell Biology, Montréal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); McGill University, Department of Neurology and Neurosurgery, Montréal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)