MGH/MIT MORRIS UDALL CENTER OF EXCELLENCE IN PD RESEARCH

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Recent discoveries have pointed to a central role of the protein alpha-synuclein in the etiology of Parkinson's disease and other synucleinopathies. 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 protein-aggregate neurodegenerative diseases including Alzheimer's disease and Huntington's disease. In the first three aims of this project we will address the question: Do alpha-synuclein aggregates lead to transcriptional dysregulation, either in dopaminergic neurons or their striatal targets? 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 2 and 4). A clearer understanding of the effects of alpha-synuclein on gene expression, oxidative stress and protein misfolding could lead to novel therapeutic strategies to prevent or retard this currently incurable disease. The fourth aim is 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 3, we will use gene expression studies to examine the striatal signaling pathways, which lead to these adverse effects, in search of new targets for symptomatic treatment.