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PARTNERS IN RESEARCH: CNDR || IOA || UDALL || Penn ADC
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Animal Models of Parkinson's Dementia

Project Description

2010 Progress Report Update Parkinson's disease studies at Penn

Advances in Past Year

Publications
Virginia M-Y LeeVirginia M.-Y. Lee, PhD
Project Leader

Project Description

2010 Progress Report Update

This project tests hypotheses regarding mechanisms of alpha-synuclein toxicity and aggregate formation. Using postmortem human brain samples that are acquired and characterized in Core C, studies are conducted in this project to compare the regional distribution of alpha-synuclein, tau and A-beta neuropathology in clinically well-defined Parkinson's disease (PD), Parkinson's disease with dementia or Dementia with Lewy Bodies (PDD/DLB), and Lewy Body Variant of Alzheimer's disease (LBVAD) patients who have been followed longitudinally by Core B and studied by Projects 1 and 2.

Penn Udall Center for Parkinson's Research Public Health StatementNew transgenic (TG) mouse models with regulated over expression of wild type (WT) or mutant human alpha-synuclein will be developed that target expression to telencephalon because existing alpha-synuclein TG mouse models have early onset motor deficits that do not model PDD/DLB. Thus, these TG mice will allow behavioral and molecular studies of novel models of PDD/DLB-like cognitive impairments linked to telencephalic accumulations of alpha-synuclein pathologies.

The role of regulated over expression of tau tangles and A-beta plaques in enhancing cognitive decline in the new alpha-synuclein TG mouse models will be evaluated, and comparisons of these TG mice with human disease samples from Core C will be performed to establish verisimilitude of these models to human synucleinopathies. Taken together, the work of Project 3 will lead to more informative models of synucleinopathies and address important questions on mechanisms leading to alpha-synuclein pathologies and their contribution to brain degeneration in synucleinopathies.

Significant Scientific Advances in the Past Year

The studies from the past funding year advanced our understanding of mechanisms underlying neurodegenerative synucleinopathies. Significantly, the ongoing studies support the alpha-synuclein “transmission” hypothesis and we have established non-neuronal as well as neuronal cell-based assays and mouse models of transmission for the identification of potential therapies for PD.

Publications