| RRC ID |
84084
|
| Author |
Siddiqui AA, Merquiol E, Bruck-Haimson R, Hirbawi J, Boocholez H, Cohen I, Yan Y, Dong MQ, Blum G, Cohen E.
|
| Title |
Cathepsin B promotes Aβ proteotoxicity by modulating aging regulating mechanisms.
|
| Journal |
Nat Commun
|
| Abstract |
While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer's disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid β (Aβ) peptide is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans, we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a mechanism by which CTSB aggravates Aβ-mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.
|
| Volume |
15(1)
|
| Pages |
8564
|
| Published |
2024-10-3
|
| DOI |
10.1038/s41467-024-52540-x
|
| PII |
10.1038/s41467-024-52540-x
|
| PMID |
39362844
|
| PMC |
PMC11450018
|
| MeSH |
Aging* / genetics
Aging* / metabolism
Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Amyloid beta-Peptides* / metabolism
Animals
Caenorhabditis elegans* / genetics
Caenorhabditis elegans* / metabolism
Caenorhabditis elegans Proteins* / genetics
Caenorhabditis elegans Proteins* / metabolism
Cathepsin B* / genetics
Cathepsin B* / metabolism
Disease Models, Animal
|
| Resource |
| C.elegans |
tm12210 |
