Project description
How yeast remember a failed mating attempt may shed light on neurodegenerative disease
Proteins are large, complex molecules ubiquitous in the body serving crucial functions in virtually all biological processes. Coded by genes, once synthesised they take on complicated 3D structures that are intricately linked to the work they do. When this architecture is disrupted, it can have serious consequences. The formation of misfolded protein aggregates is a hallmark of neurodegenerative diseases. However, more recent work has shown that aggregates also promote physiological functions and can be non-toxic. MemoryAggregates is untangling the mechanisms of functional aggregate formation in yeast, a simple single-celled model system. They will then study those aggregates in 'old' yeast to see if aging affects them and how, for potential insight into functional aggregation gone awry.
Objective
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.
Fields of science
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
8092 Zuerich
Switzerland