Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins

Veena Prahlad; Richard I Morimoto

doi:10.1073/pnas.1106557108

Back

Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins

Journal article

Open access

Peer reviewed

Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins

Veena Prahlad and Richard I Morimoto

Proceedings of the National Academy of Sciences - PNAS, Vol.108(34), pp.14204-14209

08/23/2011

DOI: 10.1073/pnas.1106557108

PMCID: PMC3161566

PMID: 21844355

Files and links (1)

url

https://doi.org/10.1073/pnas.1106557108View

Published (Version of record) Open Access

Abstract

The consequence of chronic protein misfolding is the basis of many human diseases. To combat the deleterious effects of accumulated protein damage, all cells possess robust quality-control systems, specifically molecular chaperones and clearance machineries, that sense and respond to protein misfolding. However, for many protein conformational diseases, it is unclear why this quality-control system does not efficiently counter protein aggregation. Previous findings that the heat shock response in Caenorhabditis elegans is regulated by thermosensory neurons led us to consider whether neuronal activity could also be responsible for the inadequate response of an organism to chronic protein misfolding. Here we show, in animals expressing polyglutamine expansion proteins and mutant SOD-1(G93A) in intestinal or muscle cells, that the nervous system does indeed control the cellular response to misfolded proteins. Whereas polyglutamine expansion-expressing animals with WT thermosensory neurons readily express protein aggregates, leading to cellular dysfunction without concomitant up-regulation of molecular chaperones, modulation of the nervous system results in chaperone up-regulation that suppresses aggregation and toxicity. The neuronal signal is transmitted through calcium-activated dense core vesicle neurosecretion. Cell-nonautonomous control of chaperone expression by the thermosensory neurons allows C. elegans to respond differently to acute stress such as heat shock, and chronic stress caused by the expression of misfolded proteins, suggesting that neuronal signaling determines the course of cellular proteotoxicity.

Heat-Shock Response - drug effects

Temperature

Neurosecretion - drug effects

Secretory Vesicles - metabolism

Caenorhabditis elegans Proteins - metabolism

Neurons - cytology

Heat Shock Transcription Factors

DNA-Binding Proteins - metabolism

Peptides - toxicity

Protein Structure, Quaternary

Neurons - metabolism

Neurons - drug effects

Genes, Reporter

Tropomyosin - metabolism

Caenorhabditis elegans - metabolism

Peptides - chemistry

Mutation - genetics

Protein Folding

Trinucleotide Repeat Expansion

Transcription Factors - metabolism

Up-Regulation - drug effects

Animals

Caenorhabditis elegans - cytology

Caenorhabditis elegans - drug effects

Secretory Vesicles - drug effects

Nerve Net - metabolism

Intestines - cytology

Details

Title: Subtitle: Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins
Creators: Veena Prahlad - Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA
Richard I Morimoto
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.108(34), pp.14204-14209
Publisher: United States
DOI: 10.1073/pnas.1106557108
PMID: 21844355
PMCID: PMC3161566
ISSN: 0027-8424
eISSN: 1091-6490
Grant note: R01 AG026647 / NIA NIH HHS
Language: English
Date published: 08/23/2011
Academic Unit: Iowa Neuroscience Institute; Biology
Record Identifier: 9983992000102771

Metrics

15 Record Views

114 Times Cited - Web of Science

See more details