Introduction: At least, 2.4 million traumatic brain injury (TBI) related hospital visit each year in USA and WHO predicting that TBI will be the third leading cause of death and disability worldwide by 2020 (Hyder, Wunderlich et al. 2007, Centers for Disease and Prevention 2013). Approximately one percent Americans older than 60 years old are diagnosed with Parkinson’s disease (PD)(Gazewood, Richards et al. 2013). Millions of them have to adapt to the extensive long-term disability, but its impact does not end there. They often have to depend on other people’s continuous support to survive that significantly impacts our healthcare burden (Stacey L. Kowal 2013). A new meta-analysis and other recent studies provide support for the association of history of head injury (e.g., boxing as in Muhammad Ali’s case leading to PD symptoms) with a higher risk of PD (Goldman, Tanner et al. 2006, Lee, Bordelon et al. 2012, Harris, Shen et al. 2013, Jafari, Etminan et al. 2013). But the pathological link between TBI and PD remains not fully understood and α-synuclein (α-Syn) may play a crucial role (Shahaduzzaman, Acosta et al. 2013). The overall hypothesis for this project is that repeated mild TBI or a moderate TBI when combined with targeted PD gene α-Syn mutations will magnify the pathological link between TBI and PD by accelerating accumulation of α-Syn via altering mitochondrial function and inducing neuroinflammation. Although genetic PD animal models allow us evaluations of the specific aspects of PD pathogenesis, no study has been conducted to determine the progression of the pathology and behavioral deficits in α-Syn transgenic mice after TBI. The studies proposed in this grant application will examine whether α-syn contributing to the TBI and PD pathological overlap. If we can determine the pathological link then we can design appropriate pharmacological therapies that can modulate the interaction between α-Syn mutations and TBI.
Specific Aim: Hypothesis: α-synuclein mutations will magnify the pathological link between TBI and PD. An age-dependent increased expression of α-Syn protein in the brain with a progressive motor deficits starting predominantly at 9 month of age was reported in α-Syn transgenic mice (tg) (Amschl, Neddens et al. 2013). There are no studies that have determined the role of α-Syn protein accumulation on the behavioral and pathological effects of TBI in α-syn transgenic mice. Our group recently reported that TBI precipitates AD-pathology and cognitive deficits in transgenic 3xTg-AD mice (Tajiri, Kellogg et al. 2013). In this study we examine motor recovery and a detail time course of the development of Parkinson’s-like pathology in α-Syn transgenic mice brain after inducing moderate TBI. Thirty-six adult (9 mo) mice (18 transgenic and 18 non-transgenic controls) will be use for this study. Animals will be subjected to moderate TBI using controlled cortical impact (CCI) model. Prior to TBI and at 2, 4, and 8 weeks...
