One of the most direct explanations for the underlying cell dysfunction and pathologies in Parkinson's disease (PD) and Lewy body etiologies begins with primary disturbances from lipids and other stressors, which in turn can produce protein elevation and aggregation. Lewy body inclusions, widely believed to be predominantly composed of proteinaceous filaments, are strongly co-labeled by neutral lipid stains. Importantly, recent ultrastructural findings demonstrate that Lewy bodies and neurites in PD post-mortem brain are in fact composed of abundant membranous structures, abnormal vesicles and autophagosome-like structures, in addition to disrupted cytoskeletal elements and dysmorphic mitochondria. Focus and analysis of intracellular lipids and dysfunctional lipid transport as primary mechanisms in concert with inflammatory processes for PD and Lewy body dementias (LBD) can provide a more guided, realistic, and insightful understanding of pathogenic pathways to be able to intervene effectively in these diseases, than current attempts that only focus on protein aggregation.

The primary focus area of this application is to determine cellular mechanisms producing degeneration that lead to the clinical non-motor symptoms of Parkinson's disease. Lipid and lipid transport abnormalities potentially cause these PD, Parkinson's disease dementia (PDD), LBD, and age-related dementias. The work provided by this project can result a transformational biological understanding of the mechanisms that are involved in lipid disequilibrium leading to non-motor symptoms in PD, PDD, and LBD. For example, cognitive decline is a common non-motor feature of PD in late stages, and an important therapeutic target. Significantly, ~80% patients with PD progress to dementia after the movement disorder, and there is no treatment. Providing the most realistic description of cell dysfunction that leads to PD degeneration and LBD is the scientific cornerstone of any future therapeutics. The proposed experiments will provide a long-term benefit to the field by establishing non-dopaminergic cellular systems to investigate glycosphingolipid changes that have been shown in clinical, genetic and idiopathic forms of PD and LBD to be highly likely to be responsible for non-motor symptoms of these clinical syndromes.

The planned experiments will generate results relevant to cellular dysfunction, the molecular and biochemical pathways involved and potential molecular biomarkers. This can be translated to new treatments for non-motor symptoms in PD and related disorders by giving new targets and biomarkers for exploratory endpoints in patients. It is essential to provide accurate cellular experimental modeling of neuronal and glial interactions reflecting underlying cellular dysfunction that over time leads to protein abnormalities, synaptic and immune mediated cell loss. This cellular road map is significant for pharmacological and biological interventions against the dysfunction and degeneration that underlies non-motor symptoms. The proposed work is of critical importance. Only with accurate biological information and insight can future clinical examination and clinical trials be conducted with a high chance of success. The proposed project will increase future clinical opportunities with new biological and pharmacological targets for reduction of degeneration and central and peripheral non-motor symptoms.