A conserved mechanism of gene regulation during stress is the phase separation of mRNA and proteins into membrane-less compartments termed messenger ribonucleoprotein (mRNP) granules. Recent research has implicated aberrant formation of these granules in the pathology of a variety of neurodegenerative diseases. It has been proposed that mislocalization of mRNAs and proteins to these pathological inclusions can cause a toxic gain-of-function through altered gene expression control. Our research program aims to use the formation of mRNP granules during glucose starvation in yeast to elucidate basic mechanistic principles about the formation and function of these membrane-less compartments as well as to apply the knowledge and technical expertise from yeast to understand how phase separation of RNA-binding proteins associated with neurodegenerative diseases impinge upon gene expression in mammalian cells. This research builds on our discovery that during stress, transcription and translation can be coupled, as promoter elements can determine the localization of mRNAs to mRNP granules, thereby impinging on their subsequent translatability. Our strategy will take a two-part approach. The first direction will focus on elucidating the mechanism by which promoter elements in the nucleus can direct the localization of mRNAs to mRNP granules in the cytoplasm. Second, we will explore the function that this differential localization has on the gene expression of yeast and mammalian cells. This research will give insight into basic questions of what specifies mRNA localization to membrane-less compartments and how this affects the gene expression of the cell, which is important for understanding the effects that toxic mRNP aggregates may have on cells during neurodegeneration.
It has recently emerged that in a number of debilitating neurodegenerative diseases RNAs and proteins become mislocalized to pathological aggregates. The proposed research will explore the mechanism by which RNAs can be selectively localized to RNA/protein aggregates as well as the effects this has on protein expression in the cell. In the long term this research may give us greater understanding of the formation and function of these toxic aggregates during neurodegeneration.
