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.