Neuronal signaling modulates protein homeostasis in Caenorhabditis elegans post-synaptic muscle cells

Susana M. Garcia, M. Olivia Casanueva, M. Catarina Silva, Margarida D. Amara, Richard I. Morimoto*

*Corresponding author for this work

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Protein homeostasis maintains proper intracellular balance by promoting protein folding and clearance mechanisms while minimizing the stress caused by the accumulation of misfolded and damaged proteins. Chronic expression of aggregation-prone proteins is deleterious to the cell and has been linked to a wide range of conformational disorders. The molecular response to misfolded proteins is highly conserved and generally studied as a cell-autonomous process. Here, we provide evidence that neuronal signaling is an important modulator of protein homeostasis in post-synaptic muscle cells. In a forward genetic screen in Caenorhabditis elegans for enhancers of polyglutamine aggregation in muscle cells, we identified unc-30, a neuron-specific transcription factor that regulates the synthesis of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). We used additional sensors of protein conformational states to show that defective GABA signaling or increased acetylcholine (ACh) signaling causes a general imbalance in protein homeostasis in post-synaptic muscle cells. Moreover, exposure to GABA antagonists or ACh agonists has a similar effect, which reveals that toxins that act at the neuromuscular junction are potent modifiers of protein conformational disorders. These results demonstrate the importance of intercellular communication in intracellular homeostasis.

Original languageEnglish (US)
Pages (from-to)3006-3016
Number of pages11
JournalGenes and Development
Volume21
Issue number22
DOIs
StatePublished - Nov 15 2007

Keywords

  • Cholinergic neurons
  • GABAergic neurons
  • Polyglutamine aggregation
  • Protein misfolding
  • Protein polymorphisms

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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