Cathepsin B promotes Aβ proteotoxicity by modulating aging regulating mechanisms

Atif Ahmed Siddiqui, Emmanuelle Merquiol, Reut Bruck-Haimson, Joud Hirbawi, Hana Boocholez, Irit Cohen, Yonghong Yan, Meng Qiu Dong, Galia Blum, Ehud Cohen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)8564
Number of pages1
JournalNature Communications
Volume15
Issue number1
DOIs
StatePublished - 3 Oct 2024

Bibliographical note

Publisher Copyright:
© 2024. The Author(s).

Fingerprint

Dive into the research topics of 'Cathepsin B promotes Aβ proteotoxicity by modulating aging regulating mechanisms'. Together they form a unique fingerprint.

Cite this