Abstract Ellen Nollen

Regulation of toxic protein aggregation in age-related neurodegenerative diseases

Toxic aggregation-prone disease proteins are thought to play a major role in the pathology of several age-related neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. We aim to uncover molecular pathways that regulate disease-protein toxicity and aggregation.

With genome-wide genetic screens using a small animal model for protein aggregation diseases, the nematode C. elegans, we have identified a variety of modifiers of protein aggregation and toxicity, which includes MOAG-4/SERF1,2. Depletion of MOAG-4 in C. elegans suppresses aggregation and toxicity of polyglutamine, alpha-synuclein, and amyloid-beta, suggesting that MOAG-4 is a general regulator of protein aggregation. This function is evolutionarily conserved in human SERF1 and SERF2, depletion of which suppresses mutant huntingtin aggregation in a neuroblastoma cell line. Purified MOAG-4, SERF13, and SERF2 can catalyze amyloid formation of mutant huntingtin exon-1 and alpha-synuclein in a test tube, suggesting that MOAG and SERFs are direct regulators of amyloid formation. How MOAG and SERFs regulate these activities remains to be established. Here I will report on our progress to understand the functions of MOAG-4 and SERFs and on other modifiers of protein aggregation and toxicity that we have identified.