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.

Public Health Relevance

Spinocerebellar Ataxia Type 1 (SCA1) is an adult onset neurodegenerative disease for which there is no treatment. We have discovered that the neurotrophic and angiogenic factor VEGF (Vascular Endothelial Growth Factor) is transcriptionally down-regulated in the SCA1. In this proposal we seek to elucidate the role of VEGF in SCA1 pathogenesis and test its potential as a therapeutic agent.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS082351-01A1
Application #
8631893
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gwinn, Katrina
Project Start
2013-08-15
Project End
2018-06-30
Budget Start
2013-08-15
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$378,780
Indirect Cost
$133,615
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Venkatraman, Anand; Hu, Yuan-Shih; Didonna, Alessandro et al. (2014) The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Hum Mol Genet 23:3733-45