New evidence indicates that distinct mutations cause familial Parkinson's disease (PD) by mechanisms that may also operate in sporadic PD. These new data point to the importance of cell dysfunction preceding cell death and to the involvement of non-dopaminergic neurons in the disease. Accordingly, identifying mechanisms of cellular dysfunction that are common to multiple causes of PD may offer new therapeutic targets to halt or reverse the course of the disease. This renewal application for the UCLA UDALL Parkinson Disease Center of Excellence focuses on studies of progression of dysfunction, in complementary models expressing PD-causing mutations, and in a well characterized patient population. The center consists of 5 projects supported by an administrative core and a mouse genetics core. In the first three projects we propose to continue coordinated multidisciplinary work supported by the current award to characterize the progression of motor and non-motor behavioral anomalies and neuropathology (project 1), anomalies of neurotransmitter release (project 2) and of synaptic function (project 3) in genetic mouse models of PD, including novel models based on BAG technology. These projects will be complemented by the addition of cellular models (project 4) to analyze the mechanisms of cellular dysfunction leading to the phenotypes observed in the mouse. Studying progression of dysfunction will also be the focus of the new patient oriented component of the Center. In this project (project 5), we will conduct clinical longitudinal studies of disease phenotype after diagnosis, including psychiatric and cognitive co-morbidities. This will be coupled to the development and validation of an improved health-related quality of life assessment tool. These patient oriented studies will provide crucial clinical data for future analyses of genetic material from the same patients and for the translation of our basic research efforts into improved patient care. To identify the cellular alterations leading to neurodegeneration in PD, the UCLA UDALL Parkinson Disease Center of Excellence will focus on early manifestations of the disease occurring before the onset of motor symptoms and their progression. Integrating experimental models and clinical studies, the goal of our center is to understand the mechanisms of these cellular dysfunctions in order to spur the development of therapeutic strategies able to stop the disease process. Project 1 Title: Progression of Behavioral and Pathologic Defects Preceding DA Cell Death in Mouse Models of PD PI: Marie-Francoise Chesselet, MD, PhD DESCRIPTION (provided by applicant): New evidence indicates that distinct mutations cause familial Parkinson's disease (PD) by mechanisms that may also operate in sporadic PD. During the current funding period we have identified cellular dysfunction without cell death in mice expressing various mutations known to cause PD in humans. In this renewal application we will test the hypothesis that common mechanisms of dysfunction may be induced by distinct mutations and offer therapeutic targets for treatment at early stages of the disease, before further cell death causes irreversible damage. Project 1. 2. and 3 form the continuation of the current award and will continue to use a multidisciplinary approach to uncover the mechanisms of neuronal dysfunction in existing and novel mouse models.
In specific aim 1 of project 1 we will determine the progression of behavioral deficits and neuropathology in already available mice overexpressing alpha-synuclein under different promoters and parkin KO mice. We will use a battery of sensitive motor tests we have developed to assess the motor phenotype of the mice, and will extend this analysis to non-motor behaviors because related symptoms can have a major impact on patient quality of life, as examined in project 5 of the Center. We will use immunohistochemistry to determine the progression of alpha-synuclein pathology and glial activation throughout multiple brain regions known to be affected in PD, and to detect anomalies in the expression of proteins involved in neurotransmitter release and examined in project 4 of the Center. We will use ligand binding and molecular approaches to identify dysregulation of dopaminergic transmission that will be further examined with neurochemical approaches in project 2 and with electrophysiology in project 3. Finally, eventual cell loss in brain regions that are affected in PD (locus coeruleus, ventral medulla, nigrostriatal dopaminergic neurons) will be assessed in older animals with unbiased stereology.
In specific aim 2, we will extend this analysis to novel mouse models generated in the Mouse Genetics Core with state of the art BAG technology. These include a mouse model expressing a parkin mutation shown to cause the loss of dopaminergic neurons in Drosophila. These mice will be characterized with the same methods described above, before being further analyzed in projects 2 and 3. Studies in project 1 will parallel longitudinal clinical studies of project 5 that examine disease progression in PD patients, including psychiatric and cognitive comorbidity. They will provide critical information on the time course of the deficits and new models for projects 2 and 3 and test in an in vivo mammalian system the hypotheses generated in cellular models in project 4 of the Center.
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