Age-related neurodegenerative diseases are a class of incurable diseases that result in the progressive degeneration of neuronal cells. Recent research has pointed to a role for RNA-binding proteins in age- related neurodegenerative diseases: as many RNA-binding proteins have aggregation-prone intrinsically disordered regions, they accumulate in pathological inclusions of various neurodegenerative diseases, and mutations in a number of RNA-binding proteins have been linked to neurodegenerative diseases. For many RNA-binding proteins linked to neurodegenerative diseases they also become concentrated into mRNP granules during stressful conditions. This formation of mRNP granules during stress is beneficial to cells, as disruption of these granules sensitizes cells to a variety of stressors. Our hypothesis is that mRNP granules initially form as non-toxic, potentially beneficial structures during the aging process, but that they undergo a pathological transition that leads to cell death. This proposal seeks to establish a model system for this pathological transition using yeast in combination with microfluidics to follow the formation and transition of mRNP granules during aging. To accomplish this, we will (Aim 1) build on our preliminary data exploring the pathogenicity of large age-induced mRNP granules using microfluidics and fluorescent microscopy to follow single yeast cells across their entire lifespan. Secondly, we will (Aim 2) identify markers for this pathological transition by measuring changes in the material state and macromolecular composition of age-induced mRNP granules. In the long term these markers will help to elucidate the mechanistic details of this transition. Together this system will establish a new paradigm to understand basic details on how mRNP granules can transition from non-toxic, potentially beneficial structures to pathological inclusions that drive the degeneration of cells. As many genes and pathways are conserved from yeast to mammals, including pathways that affect aging, this research may point to new targets to help ameliorate neurodegenerative diseases in humans.
For a number of age-related neurodegenerative diseases RNA-binding proteins are misregulated and become concentrated into protein aggregates, yet this concentration of RNA-binding proteins has been found to be beneficial during times of stress. This proposal aims to establish a model system for the transition of RNA-binding proteins from beneficial aggregates to pathological structures during aging.
