The Effects of Traumatic Brain Injury in Alpha Synuclein and Dopamine Regulation

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) occurs in the United States at an incidence of 200 per 100,000 people annually, causing long lasting functional and cognitive deficits due to disruptions of various neurotransmitter systems, including dopamine (DA). Based on our past studies and findings in the literature, TBI may induce both DA increase in neurons and aggregation of a-synuclein (AS). AS aggregation can induce dysregulation of DA synthesis and reuptake leading to excess DA intracellularly, and intracellular DA excess can lead to AS aggregation. It is clear from these evidences that DA and AS regulation may be interrelated. Clarifying the link between AS pathology and DA dysfunction will improve our understanding of the mechanism of cognitive deficits following TBI and contribute to development of therapeutic strategies to prevent and minimize DA neurotransmission deficits. Furthermore, it may provide us with an insight into how TBI may lead to future risk of neurodegenerative diseases like synucleinopathies. We hypothesize that the acute DA increase after TBI may be a significant contributor to AS aggregation, and this aggregation of AS may furthermore contribute to dysregulation of DA. To support this hypothesis. Specific Aim 1 will examine the effect of inhibiting DA synthesis or metabolism pharmacologically to prevent AS aggregation due to acute tissue DA increase after TBI. Western blotting and immunohistochemistry will be performed to confirm aggregation of AS. Specific Aim 2 will examine the effect of AS aggregates on DA regulation by comparing the differences between wild type and AS knockout mice in the levels and activities of enzymes regulating DA as well as level and release of DA itself. Enzyme levels will be measured by Western blots and enzyme activities will be assessed by measuring the products by high performance liquid chromatography. High performance liquid chromatography and microdialysis in vivo will be used to confirm the levels and release of DA. This project investigates how the loss of regulation of neurotransmitter dopamine occurring after TBI may be due to the affects of pathological changes in a-synuclein protein. Understanding this mechanism will help us develop therapeutic strategies to treat functional deficits after TBI and possible future development of neurodegenerative diseases.