Cathepsin B promotes Aβ proteotoxicity by modulating aging regulating mechanisms.

Autor: Siddiqui AA; Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada (IMRIC) The Hebrew University, Jerusalem, 9112001, Israel., Merquiol E; Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, 9112001, Israel., Bruck-Haimson R; Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada (IMRIC) The Hebrew University, Jerusalem, 9112001, Israel., Hirbawi J; Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada (IMRIC) The Hebrew University, Jerusalem, 9112001, Israel., Boocholez H; Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada (IMRIC) The Hebrew University, Jerusalem, 9112001, Israel., Cohen I; Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada (IMRIC) The Hebrew University, Jerusalem, 9112001, Israel., Yan Y; National Institute of Biological Sciences (NIBS), 102206, Beijing, China., Dong MQ; National Institute of Biological Sciences (NIBS), 102206, Beijing, China., Blum G; Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, 9112001, Israel. galiabl@ekmd.huji.ac.il., Cohen E; Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada (IMRIC) The Hebrew University, Jerusalem, 9112001, Israel. ehudc@ekmd.huji.ac.il.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Oct 03; Vol. 15 (1), pp. 8564. Date of Electronic Publication: 2024 Oct 03.
DOI: 10.1038/s41467-024-52540-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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