The aim of this proposal is to develop a molecular understanding of disruption of RNA metabolism in repeat expansion disorders. Unstable repeat expansions underlie over 30 genetically inherited diseases including fragile X syndrome, myotonic dystrophy, Huntington's disease and amyotrophic lateral sclerosis. In many of these diseases, the repeats are in the non-coding regions of the genome and the transcribed RNA accumulates as inclusions in neurons and other affected cell types. Thus, a prevailing model is that these diseases are caused by an RNA gain-of-function mechanism, where RNA assumes toxic properties leading to cytotoxicity and tissue degeneration. However, the molecular mechanisms of RNA foci formation remain poorly understood, and it is not currently known how the repeat expansions confer this gain-of-function behavior to the RNA. This project will apply a suite of interdisciplinary approaches to understand the molecular basis of RNA foci formation. The working hypothesis is that the sequence specific properties of the RNA alone are sufficient to induce RNA aggregation, and this RNA aggregation leads to foci formation. Biophysical underpinnings of RNA aggregation will be characterized in vitro using reconstitution approaches. Model cell culture systems will be used to study the effect of aging and environmental insults in promoting RNA foci formation and cytotoxicity. Finally, the cell culture systems will be used to screen for compounds that inhibit foci formation. The candidate for this Pathway to Independence Award is a biophysicist with expertise in microscopy and has developed biochemical methods to characterize RNA aggregation in vitro. Through this mentored training grant, the candidate will gain additional training in neuroscience and aging research, which will be essential to translate the in vitro findings to clinically relevant disease models. The candidate will work with neuroscientists and clinician-scientists at UCSF who have established programs in neurodegenerative diseases. Candidate's primary mentor, Prof. Ron Vale, is a renowned cell biologist. The training facilitated by this grant will equip the candidate with a suite of unique interdisciplinary skills at the nexus of soft matter physics, cell biology and neuroscience, while working towards understanding an important class of genetic disorders with no known cure.
Repeat expansion mutations cause over 50 inherited neurological diseases including Huntington's disease, fragile X-syndrome and ALS. Currently no cures are available for these genetically inherited diseases. In this project, we propose to investigate the biophysical properties of RNA products of these mutations, and understand how it contributes to the disease pathology. A refined molecular understanding of toxic RNA as proposed in this work, should enable us to design treatments for these diseases and contribute to our understanding of aging and environmental factors that may lead to neurodegenerative disorders.