Mechanism of Whi3 Aggregation and its Age-dependent Malfunction

ended

Age-associated neurodegenerative diseases are characterised by the irreversible pathological aggregation of proteins with low complexity (LC) sequences. In contrast, cells can exploit LC protein aggregation to help them adapt to changing environments. The factors that determine whether an aggregate is functional or pathological are unclear. How do cells control protein aggregation? Are age-associated diseases caused by loss of control over functional protein aggregates? To address these questions, we will study how yeast cells induce aggregation of Whi3, an LC RNA-binding protein, in order to memorise failed mating attempts. Using mass spectrometry, fluorescence microscopy and biochemical assays, we will determine whether post-translational modifications, RNA-binding and protein sequence affect Whi3 aggregation and function. We will then characterise the material properties and structures of Whi3 aggregates using cryo-electron tomography. Once we understand how cells control Whi3 aggregation, we will investigate whether this regulatory mechanism deteriorates in old cells, and whether the properties and structures of age-induced aggregates differ from their functional counterparts. These studies will improve our understanding of the largely unexplored phenomenon of functional protein aggregation, and how ageing promotes the uncontrolled protein aggregation underlying neurodegenerative diseases.