National Parkinson Foundation Grant

Travis Dunckley, Ph.D. from TGen;

Charles H. Adler, MD, PhD and John N. Caviness, MD from Mayo Clinic

This grant proposal seeks to identify the genes that contribute to the formation of cortical Lewy bodies and to dementia in Parkinson’s disease (PD). We will apply sophisticated single cell expression profiling techniques to identify dysregulated, neuronally expressed genes that are altered during the course of PD, PD with dementia, and in Lewy bodies specifically. We have ongoing collaborations with expert PD clinical diagnosticians and neuropathologists to ensure the inclusion of well-defined and stratified patient cohorts to yield only the most relevant expression correlates. We have an established and validated statistical approach to identify reliable pathologic expression correlates utilizing permutational statistics algorithms. Importantly, we have successfully applied this approach already to a study of neurofibrillary tangles (NFTs) in Alzheimer’s disease and identified numerous novel genes that are dysregulated in NFTs. This expression profiling effort will be completed within one year and all data made publicly available via the NINDS/NIMH microarray consortium website. Thereafter, years 2 and 3 will involve immunohistochemical validation (first half of year 2) and measures of the functional consequences of perturbing expression of these genes on cell viability and α-synuclein expression, which has been associated with PD and LB formation. Our established clinical network of collaborators (Dr. Charles Adler, Dr. John Caviness, Dr. Marwan Sabbagh, Dr. Thomas Beach) will continue to provide valuable input into data interpretation at this stage of the research effort to ensure that results are interpreted with the highest clinical relevance possible. In addition, an expert bioinformaticist (John Pearson) will facilitate rapid interpretation of significant expression correlates into biological pathways and processes using INGENUITY and GeneGo software, as well as data parsing tools, to mine available databases for relevant information on all gene candidates. This proposal will identify novel genes associated with LB pathology and dementia in PD and, more importantly, novel targets for the discovery of interventions to treat or prevent the onset of PD with dementia.