Cellular protein damage control: regulation of aging-related protein aggregation and toxicity
The accumulation of aggregation-prone disease proteins in aggregates in the brain is the major pathological hallmark of several age-related neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Recent findings suggest that the pathology spreads throughout the brain by cell-to-cell transmission of the disease proteins. To understand the disease mechanisms we aim to uncover the cellular pathways that regulate disease-protein toxicity, aggregation, and spreading.
With genome-wide genetic screens in C. elegans models for protein aggregation diseases, we have previously identified a variety of regulators of protein aggregation and toxicity. Opening up exciting new avenues for research is our identification of a modifier of aggregation, which we named MOAG-4/SERF, as a regulator of age-related proteotoxicity. MOAG-4/SERF appears to act independently of classical pathways that degrade proteins or prevent their aggregation, but its molecular role remains to be determined.
We hypothesize that MOAG-4/SERF represents one of more previously un-described regulatory pathways of age-related proteotoxicity in neurodegenerative diseases. To address this hypothesis our main research goals are: i) to uncover the function of the pathway in which MOAG-4 is operating, ii) to uncover other pathways regulating age-related proteotoxicity, iii) to establish C. elegans models to identify processes involved in the cell-to-cell transmission of aggregation-prone proteins, iv) to establish the evolutionary conservation of proteotoxicity regulating pathways and their role in human disease.
By combining the power of C. elegans genetics with the development of cell-biological tools to visualize and monitor aggregation, toxicity and cell-to-cell transmission in living and aging worms and in patient-derived cells, we aim to provide new insights into the early molecular events of aging-associated neurodegenerative diseases and identify targets for treatment.
