TY - JOUR
T1 - Cathepsin B promotes Aβ proteotoxicity by modulating aging regulating mechanisms
AU - Siddiqui, Atif Ahmed
AU - Merquiol, Emmanuelle
AU - Bruck-Haimson, Reut
AU - Hirbawi, Joud
AU - Boocholez, Hana
AU - Cohen, Irit
AU - Yan, Yonghong
AU - Dong, Meng Qiu
AU - Blum, Galia
AU - Cohen, Ehud
N1 - Publisher Copyright:
© 2024. The Author(s).
PY - 2024/10/3
Y1 - 2024/10/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85205605222&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-52540-x
DO - 10.1038/s41467-024-52540-x
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C2 - 39362844
AN - SCOPUS:85205605222
SN - 2041-1723
VL - 15
SP - 8564
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -