(RELINQUISHED) CAREER: Understanding Spinocerebellar Ataxia Type 1 Pathogenesis

DESCRIPTION The long term goal of this award is to support Dr. Puneet Opal in his efforts to become an independent clinician scientist advancing our understanding of, and ability to treat, neurodegenerative diseases. He must build on his strong neuroscience and neurology background with intensive training in neurogenetics and the creation and analysis of animal models for human diseases. Dr. Zoghbi's laboratory, pioneering as it has been in the field of neurogenetics, is an ideal environment for such training. This project focuses on the pathogenesis of spinocerebellar ataxia type I (SCAI), a dominantly inherited disease belonging to a family of disorders caused by the expansion of a glutamine repeat tract. SCAI has proven an excellent model of polyglutamine toxicity, and the Scal mouse line is arguably the most thoroughly characterized of all polyglutamine animal models. How the expanded protein damages neurons, and why only certain populations of neurons are vulnerable in a given polyglutamine disease, are important issues to be resolved, from both a basic science and a clinical standpoint. Evidence from cell culture, Scal fly and mouse models suggests that expanded ataxin-1, unlike its wild-type counterpart, tends to misfold and resist degradation. The candidate will test the ability of protein chaperones -members of the family of heat shock proteins that are known to help modulate and clear misfolded proteins-to mitigate neurodegeneration. Since it is likely that ataxin-1 interacts with cell-specific proteins that make Purkinje cells vulnerable to degeneration, the candidate will also probe the role of the leucine-rich acidic nuclear protein (LANP) in SCAI pathogenesis. This protein's high expression in Purkinje cells and strong interaction with mutant ataxin-1 suggest it might confer upon these cells selective vulnerability. Aberrant protein folding and selective neuronal damage are hallmarks of not just the polyglutamine disorders but also diseases such as Parkinson's and Alzheimer's, so the results of this project should have broad ramifications for a number of neurodegenerative conditions