Date of Award

6-2013

Degree Name

Master of Science

Department

Biological Sciences

First Advisor

Dr. Charles F. Ide

Second Advisor

Dr. John M. Spitsbergen

Third Advisor

Dr. Cindy Linn

Keywords

CXCR4, SDF-1, Purkinje cells, MSA, apoptosis

Access Setting

Masters Thesis-Open Access

Abstract

Multiple System Atrophy (MSA) is a sporadic, neurodegenerative disease that consists of three conditions: autonomic dysfunction, Parkinsonism and cerebellar ataxia. Our lab conducted an Affymetrix global gene expression analysis using pons tissue of MSA patients to determine genes that are differentially expressed when compared to non- MSA controls. This study identified upregulated genes, including the C-X-C chemokine receptor type 4, CXCR4, to which stromal cell-derived factor-I (SDF-1) is the natural ligand. The CXCR4/SDF-1 signaling pair has been sho.wn to play multiple roles in the brain, such as inducing neuronal apoptosis and promoting leukocyte recruitment during inflammation. The MSA cerebellum presents a significant decrease in Purkinje cells, which are responsible for coordinating motor movement; MSA patients suffer from cerebellar ataxia. The study described in this thesis is the first to quantitatively demonstrate that both CXCR4 and SDF-1 protein levels are significantly upregulated in MSA Purkinje cells compared to controls. Furthermore, the apoptotic protease Caspase 3 is also expressed at a significantly higher level in Purkinje cells of MSA patients compared to controls. These findings suggest that CXCR4/SDF-1 are associated with neuronal apoptosis. Intervention of this pair's signaling cascade has the potential as being a therapeutic target in MSA and other diseases affected by neuronal loss.

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