A neuronal GPCR modifies neuropeptide signaling to suppress proteostasis in distal tissues
- 1Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel–Canada, The Hebrew University of Jerusalem, Jerusalem, Israel.
- 2Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
Abstract
The proteostasis network (PN) safeguards the integrity of proteins by promoting various cellular activities. However, with aging, the PN’s competence declines and aggregated proteins accrue within cells. This process underlies the development of neurodegenerative disorders such as Alzheimer’s and Huntington’s diseases. While the PN functions within cells, proteostasis is regulated across the organism by intertissue communication, which is partially governed by neurons. We previously found that reducing the expression of gtr-1 , which encodes a neuronal heterotrimeric guanine nucleotide–binding protein–coupled receptor, mitigates the toxicity of the Alzheimer’s disease cause, Aβ peptide. Here, we investigated the mechanism that is acted upon the knockdown of gtr-1 and found that it differentially modulates gene expression profiles, including of neuropeptide-coding genes, and dissimilarly modifies protein aggregation in worms that express distinct proteotoxic proteins. The knockdown of gtr-1 also enhances protein degradation. These findings highlight the roles of neuropeptides as organismal coordinators of proteostasis in the face of distinct proteotoxic challenges.
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BibTeX
@article{hirbawi2026neuronal,
title = {{A neuronal GPCR modifies neuropeptide signaling to suppress proteostasis in distal tissues}},
author = {Joud Hirbawi and Adam Zaretsky and Huadong Zhu and Uri Goshtchevsky and Gourab Dey and Emmanuelle Merquiol and Atif Ahmed Siddiqui and Irit Cohen and Galia Blum and Ehud Cohen},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.ady6048},
url = {https://www.science.org/doi/10.1126/sciadv.ady6048},
note = {CC BY},
}
RIS
TY - JOUR
TI - A neuronal GPCR modifies neuropeptide signaling to suppress proteostasis in distal tissues
AU - Joud Hirbawi
AU - Adam Zaretsky
AU - Huadong Zhu
AU - Uri Goshtchevsky
AU - Gourab Dey
AU - Emmanuelle Merquiol
AU - Atif Ahmed Siddiqui
AU - Irit Cohen
AU - Galia Blum
AU - Ehud Cohen
PY - 2026
DA - 2026/10/09
JO - Science Advances
DO - 10.1126/sciadv.ady6048
UR - https://www.science.org/doi/10.1126/sciadv.ady6048
AB - The proteostasis network (PN) safeguards the integrity of proteins by promoting various cellular activities. However, with aging, the PN’s competence declines and aggregated proteins accrue within cells. This process underlies the development of neurodegenerative disorders such as Alzheimer’s and Huntington’s diseases. While the PN functions within cells, proteostasis is regulated across the organism by intertissue communication, which is partially governed by neurons. We previously found that reducing the expression of gtr-1 , which encodes a neuronal heterotrimeric guanine nucleotide–binding protein–coupled receptor, mitigates the toxicity of the Alzheimer’s disease cause, Aβ peptide. Here, we investigated the mechanism that is acted upon the knockdown of gtr-1 and found that it differentially modulates gene expression profiles, including of neuropeptide-coding genes, and dissimilarly modifies protein aggregation in worms that express distinct proteotoxic proteins. The knockdown of gtr-1 also enhances protein degradation. These findings highlight the roles of neuropeptides as organismal coordinators of proteostasis in the face of distinct proteotoxic challenges.
SN - 2375-2548
ER -