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 () and Ehud Cohen ()
Additional contact information
Atif Ahmed Siddiqui: the Institute for Medical Research Israel—Canada (IMRIC) The Hebrew University
Emmanuelle Merquiol: The Hebrew University
Reut Bruck-Haimson: the Institute for Medical Research Israel—Canada (IMRIC) The Hebrew University
Joud Hirbawi: the Institute for Medical Research Israel—Canada (IMRIC) The Hebrew University
Hana Boocholez: the Institute for Medical Research Israel—Canada (IMRIC) The Hebrew University
Irit Cohen: the Institute for Medical Research Israel—Canada (IMRIC) The Hebrew University
Yonghong Yan: National Institute of Biological Sciences (NIBS)
Meng Qiu Dong: National Institute of Biological Sciences (NIBS)
Galia Blum: The Hebrew University
Ehud Cohen: the Institute for Medical Research Israel—Canada (IMRIC) The Hebrew University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-52540-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52540-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-52540-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().