The Molecular Role of SERF in Amyloid Formation:a fine line between toxicity and function

An important hallmark of most neurodegenerative diseases is the presence of misfolded proteins that can accumulate into toxic aggregates. Previous studies identified the aggregation-promoting modifier of aggregation 4 (MOAG-4) in Caenorhabditis elegans and small EDRK-rich factors (SERF)1 and SERF2 in humans. These factors were found to promote the aggregation and associated toxicity of multiple, unrelated amyloidogenic proteins. The mechanisms through which MOAG-4/SERF bind to and drive the aggregation of structurally unrelated proteins has remained elusive, as well as their endogenous functions. We showed that SERF2 interacts through charge-based interactions with amyloidogenic proteins, and accelerated the aggregation of these proteins. The highly conserved, positively charged N-terminus of SERF2, as well as negatively charged regions in amyloidogenic proteins are required for these interactions. In addition, neutralizing the charged region in MOAG-4 suppressed protein aggregation in C. elegans. Interactions between positively charged SERF2 and these negatively charged regions might induce structural conversions in amyloidogenic proteins that could enhance amyloid fibril formation.Furthermore, we identified 21 potential SERF2-interacting proteins. The identification of multiple RNA-binding proteins among our potential SERF2 interacting proteins suggests a role for SERF2 as an RNA-organizing protein in liquid-like RNA organelles. Further research is needed to confirm these interactions and to validate the exact function of SERF2 in these molecular pathways. Taken together, this thesis demonstrates the relevance of charge-based interactions between amyloidogenic proteins and amyloid-promoting factors like SERF2. In addition, it provides a basis for determining the endogenous function of SERF2