UC San Diego

The proper regulation and function of cellular stress resistance pathways are essential to the maintenance of the proteome. Impairment of these pathways leads to the accumulation of aggregates and misfolded proteins, resulting in age-associated neurodegenerative diseases. Subsequent age-onset proteotoxic damage often is accompanied by widespread changes in peripheral metabolism. Endocrine-based communication of cellular stress may play a causative role in the extensive metabolic changes seen in neurodegenerative disease. Using C. elegans models of proteotoxic stress, the impact of neuronal specific toxicity on peripheral cellular stress responses was assessed. Proposed is a neuroendocrine system of regulation on the distal response of the mitochondrial unfolded protein response (UPRmt). Genetic loss in UPRmt function blocks the response in distal mitochondria, and both neurosecretion and the nutrient- responsive neurotransmitter serotonin are required for the signal's propagation. This model of systemic stress regulation is used to evaluate the impact of other metabolic pathways in proteotoxicity and to identify novel signaling components that may play a role in the widespread pathology associated with neurodegenerative disease