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Cathepsin B promotes Aβ proteotoxicity by modulating aging regulating mechanisms

Author

Listed:
  • 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)

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.

Suggested Citation

  • Atif Ahmed Siddiqui & Emmanuelle Merquiol & Reut Bruck-Haimson & Joud Hirbawi & Hana Boocholez & Irit Cohen & Yonghong Yan & Meng Qiu Dong & Galia Blum & Ehud Cohen, 2024. "Cathepsin B promotes Aβ proteotoxicity by modulating aging regulating mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52540-x
    DOI: 10.1038/s41467-024-52540-x
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    References listed on IDEAS

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    1. David Vilchez & Ianessa Morantte & Zheng Liu & Peter M. Douglas & Carsten Merkwirth & Ana P. C. Rodrigues & Gerard Manning & Andrew Dillin, 2012. "RPN-6 determines C. elegans longevity under proteotoxic stress conditions," Nature, Nature, vol. 489(7415), pages 263-268, September.
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