The inverse correlation between polyQ length and age at onset observed in the human diseases suggests that the intrinsic biophysical properties of polyQ motifs must have a dominant role in pathology and toxicity.In young adult animals expressing polyQ in body wall muscle cells, Q is diffuse and soluble whereas Q form discrete aggregates visualized by the chimeric fluorescent YFP tag. The appearance of polyQ aggregates in neurons and muscle cells is associated with toxicity and has dramatic effects on motility. FRAP methods provide direct measures of diffusion rates of protein species that can be used to compare different cell types during development and aging, whereas FRET efficiencies measures molecular proximities in proteinprotein interactions.Neuronal Q exhibits heterogeneous properties with some ventral nerve cord neurons expressing both soluble and aggregate species, whereas other neurons. Intermediate lengths of polyQ show an agedependent aggregation phenotype of soluble protein at day and increasing numbers of aggregates in day and day of adulthood.The graph shows that there is a corresponding agedependent increase in cellular toxicity. This celltocell variation in the biophysical properties of threshold lengths of polyQ in neurons could have many explanations, including subtle differences in expression and differences in chaperones and clearance Spermine machineries or other cell typespecific modifiers.These modifiers sort into five major classes: genes involved in RNA metabolism, protein synthesis, protein folding, protein trafficking, and protein degradation.These five classes can be further sorted into two categories: genes that regulate the expression of a damaged protein, and genes involved in folding, transport, and clearance.These results reveal that the transition between soluble and aggregated states of polyQ is regulated by a much more Dopamine hydrochloride complex network that extends well beyond protein quality control.Similar results were observed with small molecule agonists and antagonists that work at the synaptic junction to effect overstimulation.These results suggest that protein homeostasis is also regulated in a cellnonautonomous manner, and reveal an important and unexpected role for the nervous system on the health of the postsynaptic cell.Aging and protein homeostasis are strongly intertwined.Genes in the insulinlike signaling pathway that regulate aging and prolong life span have been shown to be potent modulators of aggregation toxicity. Derepression of DAF in age animals extends life span and daf mutations suppress longevity.The age effects on longevity and polyQ aggregation toxicity require the DAF pathway, revealing a common genetic pathway. The role of genetic pathways that regulate life span and suppress proteotoxicity associated with multiple aggregationprone proteins suggests an important relationship between the genetics of aging and disease.The molecular interactions between these pathways are subserved, in part, by factors that detect and respond to misfolded proteins; namely, DAF, HSF, and molecular chaperones.Inhibition of HSF suppresses the ILS protection against misfolded proteins.Roles of the ILS pathway and HSF in aggregation toxicity and longevity.Both HSF and DAF are essential components and function in concert to promote longevity and to maintain protein homeostasis.Reduction of the ILS signal leads to the activation of DAF and enhancement of life span.GENES DEVELOPMENT works, while potent modifiers of aggregation toxicity must function in the context of multiple networks that regulate different aspects of protein homeostasis.

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