University of California, San Diego (UCSD)

Investigating the Role of Stress Granules in Neurodegenerative Disease

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Amyotrophic Lateral Sclerosis (ALS) is a devastating age-related neurodegenerative disease characterized by the progressive degeneration of motor neurons (MNs) in the brain and spinal cord, leading to a continuous lack of motor control and ultimately paralysis. ALS affects about 1:50,000 people with onset most commonly between 50 and 60 years of age. There are currently no effective treatments available and the disease usually leads to death within 3-5 years in a majority of patients. A common feature of ALS and many other prominent neurodegenerative diseases is the presence of abnormal intracellular protein aggregations. In recent years, the focus on aberrant protein aggregates as a central feature in ALS has further sharpened, following the observations that many common ALS-linked mutations (e.g. in TARDBP, FUS, HNRNPA2B1, C9ORF72, TIA1, etc.) alter the dynamics of cytoplasmic stress granules (SGs). SGs represent a physiological cellular response to unfavorable environmental conditions, leading to a temporary sequestration and translational arrest of the bulk of cellular mRNAs. As the link between SGs and neurodegenerative processes is becoming increasingly clear, interest is growing in the intrinsic cellular process of SG formation as a promising mechanism to study for the identification of new targets and strategies for therapeutic intervention. My work is focused on identifying currently unknown protein and RNA components of stress granules as well as understanding how SG formation in the context of ALS-linked mutations affects cellular RNA metabolism and survival. Lastly, we are pursuing small molecule screens to identify compounds that can modulate SG dynamics in a disease-specific manner.