The Age-Dependent Collapse of Proteostasis: A Polyglutamine Model for Protein Misfolding Disorders
Nosrati, Jason D.
MetadataShow full item record
Neurodegenerative disorders such as Huntington's disease, Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis have a common etiology: they are caused the age-dependent accumulation and aggregation of misfolded proteins, and the subsequent cellular damage and collapse of proteostasis. In Caenorhabditis elegans (C. elegans), this age-dependent decline in the proteostatic capacity of the cell can be abrogated by the elimination of Germline Stem Cells (GSC). Such rescue of protein quality control may therefore serve as a novel target for the treatment of protein misfolding diseases. In this study, we have used a genetic model for GSC inhibition via mutation of the g/p-1 gene in a C. e/egans model of polyglutamine (polyQ) disorders. We expressed extended polyQ chains with a fluorescent protein in muscle, intestinal and neuronal cells and observed the effects of g/p-1 deletion on proteostasis via observing protein aggregation and tissue associated toxicity. We show that toxicity of polyQ proteins in muscle and neurons, but not in intestine, was rescued by GSC arrest. Moreover, we show that the effect of GSC inhibition on polyQ aggregation is different in each tissue, and has no correlation with toxicity. We conclude that the deletion of the g/p- 1 gene does indeed rescue the collapse of proteostasis dependent toxicity, and that accumulation of aggregates per se is not a good indicator of toxicity. Because our final goal is to be able to improve protein folding in the soma without compromising fertility through GSC elimination, we have concluded by creating a viable C. elegans strain overexpressing the lipl-4 gene, a member of the kri-1 signaling pathway, and key player in GSC-dependent regulation of longevity that does not compromise fertility. The rescue of the collapse of proteostasis in this strain could be the first step towards discovering a viable pathway for treatment of several neurological disorders.