Molecular players of protein aggregation
Several neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases, are characterised by the formation of pathogenic amyloid fibrils in the brain. Several proteins in both humans and bacteria naturally organise into fibrils and demonstrate a variety of structural and regulatory functions. However, the cellular process of aggregation, its regulation and the toxicity generated are not completely understood. The scope of the EU-funded AGGREGATION (Cellular protein damage control: Interactomic analyses of MOAG-4 in C. elegans) project was to unravel the pathways of protein aggregation during neurodegeneration. The work focused on a recently identified regulator of aggregation in Caenorhabditis elegans, MOAG-4, which promotes the aggregation and toxicity of three disease proteins: PolyQ, amyloid-ß and α-synuclein. MOAG-4 is evolutionarily conserved in the human orthologues SERF1A and SERF2. Scientists studied the interaction of MOAG-4/SERF with other proteins in the cell and how these interactions can explain their role in protein aggregation. For this purpose, they looked for the interacting partners of SERF in the human proteome using the yeast two-hybrid method. They found 40 proteins that bound with high affinity. Bioinformatics analysis indicated that the majority of these proteins constituted SERF substrates and displayed a propensity to form amyloid aggregates both in vitro and in vivo. Collectively, this data indicates that SERFs serve as general regulators of aggregation for a number of proteins and not just the known disease proteins. The consortium extended their studies in C. elegans where they identified over 20 SERF orthologues and confirmed the same regulatory role for MOAG-4 as for human SERF. Future research activities will explore the potential of SERF as a target to treat protein aggregation in neurodegenerative disorders.
Keywords
Protein aggregation, neurodegenerative disorders, amyloid fibrils, MOAG-4, C. elegans
