Recent discoveries have pointed to a central role of the protein alpha-synuclein in the pathophysiology of Parkinson's disease. The mechanism by which alpha-synuclein exerts a toxic effect is unknown. One potentially crucial mechanism is transcriptional dysregulation, meaning interference with the expression of cellular genes essential for normal function. Transcriptional dysregulation has been shown to be a key mechanism in other neurodegenerative diseases including Alzheimer's and Huntington's diseases, and emerging evidence implicates similar mechanisms in PD. In the first two aims of this project we will address the question: Do alpha-synuclein aggregates in human disease or animal models lead to transcriptional dysregulation? We will use an array-based approach to perform a broad examination of this question, in addition, we will conduct a focused study of two processes that may underlie the selective vulnerability of dopamine neurons characteristic of the disease: i) mechanisms for protection against oxidative stress, and ii) chaperone mechanisms for the degradation and clearance of misfolded proteins (in collaboration with Projects by Young and Lindquist. In the third aim, we wilt use a transgenic model of synucleinopathy to determine whether restoring the expression of dysregulated genes can ameliorate the disease process.
The fourth aim i s directed at improving symptomatic therapy of the disease. The mainstay of existing therapies is dopaminergic replacement, but long term use of these drugs is associated with adverse motor effects (wearing off and dyskinesia). In collaboration with Project by Hyman, we will use gene expression studies to examine the striatal signaling pathways which lead to these adverse effects, in search a better understanding of the basic mechanisms responsible and new approaches to treatment.
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