A kinetic assessment of theC. elegansamyloid disaggregation activity enables uncoupling of disassembly and proteolysis

Abstract

Protein aggregation is a common feature of late onset neurodegenerative disorders, including Alzheimer's disease. In Alzheimer's disease, misassembly of the Aβ peptide is genetically linked to proteotoxicity associated with disease etiology. A reduction in Aβ proteotoxicity is accomplished, in part, by the previously reported Aβ disaggregation and proteolysis activities–under partial control of heat shock factor 1, a transcription factor regulating proteostasis in the cytosol and negatively regulated by insulin growth factor signaling. Herein, we report an improved in vitro assay to quantify recombinant fibrillar Aβ disaggregation kinetics accomplished by the exogenous application of C.elegans extracts. With this assay we demonstrate that the Aβ disaggregation and proteolysis activities of C.elegans are separable. The disaggregation activity found in C.elegans preparations is more heat resistant than the proteolytic activity. Aβ disaggregation in the absence of proteolysis was found to be a reversible process. Future discovery of the molecular basis of the disaggregation and proteolysis activities offers the promise of delaying the age‐onset proteotoxicity that leads to neurodegeneration in a spectrum of maladies.