Neuropeptide signaling and SKN-1 orchestrate differential responses of the proteostasis network to dissimilar proteotoxic insults

Hana Boocholez, Filipa Carvalhal Marques, Amir Levine, Noa Roitenberg, Atif Ahmed Siddiqui, Huadong Zhu, Lorna Moll, Danielle Grushko, Reut Bruck Haimson, Tayir Elami, Ehud Cohen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The protein homeostasis (proteostasis) network (PN) encompasses mechanisms that maintain proteome integrity by controlling various biological functions. Loss of proteostasis leads to toxic protein aggregation (proteotoxicity), which underlies the manifestation of neurodegeneration. How the PN responds to dissimilar proteotoxic challenges and how these responses are regulated at the organismal level are largely unknown. Here, we report that, while torsin chaperones protect from the toxicity of neurodegeneration-causing polyglutamine stretches, they exacerbate the toxicity of the Alzheimer's disease-causing Aβ peptide in neurons and muscles. These opposing effects are accompanied by differential modulations of gene expression, including that of three neuropeptides that are involved in tailoring the organismal response to dissimilar proteotoxic insults. This mechanism is regulated by insulin/IGF signaling and the transcription factor SKN-1/NRF. Our work delineates a mechanism by which the PN orchestrates differential responses to dissimilar proteotoxic challenges and points at potential targets for therapeutic interventions.

Original languageAmerican English
Article number110350
JournalCell Reports
Volume38
Issue number6
DOIs
StatePublished - Feb 2022

Bibliographical note

Funding Information:
This study was generously supported by the Israel Science Foundation (ISF) (EC#543/21), the Israeli Ministry of Science and Technology (MOST) (EC#80884), the United States-Israel Bi-national Science Foundation (BSF) (EC#2017241), and the Henri J. and Erna D. Leir Chair for Research in Neurodegenerative Diseases. F.C.M. was supported by the Portuguese Foundation for Science and Technology (fellowship #SFRH/BD/70502/2010). We thank Dr. Yael Feinstein-Rotkopf and Dr. Zakhariya Manevitch (the faculty of medicine of the Hebrew University of Jerusalem) for expert assistance in confocal microscopy. E.C. H.B. and F.C.M. designed and initiated this study, and wrote the manuscript. H.B. and F.C.M. performed most of the experimental work including strain crossing, proteotoxicity, and thrashing assays, as well as cloning and qPCR procedures. N.R. L.M. D.G. R.B.H. H.Z. and T.E.A. conducted paralysis assays and thrashing experiments. H.Z. created RNAi plasmids, A.L. performed computational analysis of RNA-seq data, and A.A.S. created transgenic worms. The authors declare no competing interests.

Funding Information:
This study was generously supported by the Israel Science Foundation (ISF) ( EC#543/21 ), the Israeli Ministry of Science and Technology (MOST) ( EC#80884 ), the United States-Israel Bi-national Science Foundation (BSF) ( EC#2017241 ), and the Henri J. and Erna D. Leir Chair for Research in Neurodegenerative Diseases. F.C.M. was supported by the Portuguese Foundation for Science and Technology (fellowship # SFRH/BD/70502/2010 ). We thank Dr. Yael Feinstein-Rotkopf and Dr. Zakhariya Manevitch (the faculty of medicine of the Hebrew University of Jerusalem) for expert assistance in confocal microscopy.

Publisher Copyright:
© 2022 The Author(s)

Keywords

  • Caenorhabditis elegans
  • SKN-1/NRF
  • aging
  • insulin/IGF cascade
  • neurodegeneration
  • neuropeptide signaling
  • proteostasis
  • proteotoxicity
  • Homeostasis/physiology
  • Proteostasis/physiology
  • Caenorhabditis elegans/metabolism
  • DNA-Binding Proteins/metabolism
  • Proteome/metabolism
  • Signal Transduction/physiology
  • Peptides/metabolism
  • Animals
  • Transcription Factors/metabolism
  • Caenorhabditis elegans Proteins/metabolism
  • Neuropeptides/metabolism

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