Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41598-021-91367-0
Keywords
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Categories
Funding
- Canadian Institutes of Health Research (CIHR) [2011MOP-243413BCA-CGAG-45097, 201610PJT-377052-PJT-CFAF-45097]
- Leaders Opportunity Fund
- Canadian Foundation for Innovation and Jewish General Hospital Foundation
- Alzheimer Society of Canada Dr. and Mrs. Spatz doctoral award
- CFI [LOF 28331]
- CIHR [OG 126137]
- FRSQ [CB 254033]
- NSERC [DG/DAS 2017-04730, USRA 552184-2020]
- FRQNT BPCA [298265]
- Canada Summer Jobs
- NLM [R01 LM012535, R01 LM011360]
- NIA [R03 AG054936, R01 AG19771, P30 AG10133, P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, U01AG046170]
- DOD [W81XWH-14-2-0151]
- NIGMS [P50GM115318]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant) [U01AG024904]
- DODADNI (Department of Defense award) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- AbbVie
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Eisai Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Lumosity
- Lundbeck
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Servier
- Takeda Pharmaceutical Company
- Transition Therapeutics
- ADNI clinical sites in Canada
- National Institute on Aging (NIA) [P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152]
- Illinois Department of Public Health
- Translational Genomics Research Institute
- National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS080820]
- CurePSP Foundation
- Mayo Foundation
- National Institute of Neurological Disorders and Stroke (National Brain and Tissue Resource for Parkinson's Disease and Related Disorders) [U24 NS072026]
- NIA (Arizona Alzheimer's Disease Core Center) [P30 AG19610]
- Arizona Department of Health Services (Arizona Alzheimer's Research Center) [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation for Parkinson's Research
Ask authors/readers for more resources
A rare Casp6N73T variant can protect against hippocampal atrophy by altering its catalysis of natural protein substrates, leading to less Casp6-mediated damage to neuronal structure and function.
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 alpha -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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