Understanding the cellular basis of Movement Disorders

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DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is one of nine late-onset neurodegenerative diseases caused by the expansion of a polyglutamine (CAG) repeat. In the case of SCA1, the pathogenic glutamine expansion affects ataxin-1 (ATXN1), a protein that plays a role in transcriptional repression. We and others have found that in SCA1 genetic mouse models, mutant ATXN1 alters gene expression as early as two weeks after birth, long before behavioral signs and other pathological events become evident. Given the early nature of these transcriptional aberrations, we predicted that altered expression of a few key genes plays a mediatory role in pathogenesis. In the course of testing this prediction, we made the unexpected discovery that ATXN1 directly regulates the expression of the angiogenic and neurotrophic cytokine VEGF and that its levels are abnormally low in the SCA1 mouse brain. Following up on this observation, we discovered that genetically increasing VEGF levels mitigates the SCA1 phenotype in the well-characterized SCA1 knock-in mouse (SCA1154Q/2Q; Q=glutamine), the best existing mouse model of SCA1. We have also demonstrated in preliminary proof-of-principle experiments that VEGF delivered pharmacologically (by intraventricular delivery of recombinant VEGF) improves the cerebellar aspects of the SCA1 phenotype, specifically the hallmark ataxia and the cerebellar dendritic pathology. Motivated by these promising results, we wish to test two related hypotheses: that VEGF is an important cytokine for maintaining neurovascular health in the context of SCA1, and that VEGF has the potential to serve as therapy for this otherwise untreatable disease. We hope that these studies will provide mechanistic insights into the pathogenesis of SCA1 and also help design clinical trials for this disease. An important ancillary outcome of these studies is that they would shed light on the basic biology of VEGF in the nervous system and provide clues to its role in other neurodegenerative syndromes.