The mechanism linking traumatic brain injury to amyotrophic lateral sclerosis

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DESCRIPTION (provided by applicant): The applicant's career goal is to become an independent scientist studying neurodegenerative disease in the fields of neuroscience and aging. A comprehensive mentoring plan with a team of mentors of diverse backgrounds will ensure the applicants career development. The proposed studies will address the link between traumatic brain injury (TBI) and amyotrophic lateral sclerosis (ALS) initiation and progression through the mechanism of accelerated protein expression and aggregation. There is increased clinical evidence linking TBI to ALS but the pathophysiological mechanisms involved in this relationship remain to be established. The proposed studies will address this gap in knowledge by determining the effect of TBI prior to disease onset on initiation and progression of ALS pathology. In fALS, the detrimental effects of the mutated SOD1 are thought to form high molecular weight aggregates. TBI also increases protein aggregation, a hallmark of neurodegenerative disease including ALS. Interestingly, another protein, transactivation response or TAR DNA Binding Protein 43 (TDP-43), forms aggregates in both ALS and TBI which suggests that protein aggregation could be a possible common mechanism. In addition, the effect of the inhibition of protein aggregation by thioflavin T (ThT), a compound that has been shown to bind protein fibrils and slow aggregation has been shown to extend lifespan potentially through the reduced protein aggregation. Based on the evidence outlined above, three specific aims address critical questions regarding the role of traumatic injury in the progression of ALS: 1) establish the effect of TBI on initiation and progression of ALS; 2) determine the impact of TBI on ALS associated protein expression and aggregation; 3) elucidate whether thioflavin T (ThT) can reduce protein aggregation and modulate ALS initiation and progression. The combined results of these investigations will result in a better understanding of the mechanism relating TBI to ALS etiology. These studies will provide training in molecular biology, animal models, immunohistochemistry, behavioral analysis and histomorphometry. The proposed studies are significant because they will explore the effects of a novel intervention thioflavin T (ThT), on the modulation of ALS associated protein expression and aggregation. The innovation of this proposal is the combination of TBI and ALS models in order to determine their collaborative effect on disease pathology. As a result, these studies will have a significant impact on our understanding of the role of TBI on the progression of neurodegenerative disease and will lead to improved treatments for TBI and ALS. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably fatal neurological disease has been recently linked to traumatic brain injury (TBI), however the pathophysiological mechanisms involved in this relationship remain to be established. The proposed studies will address this gap by determining the effect of TBI prior to disease onset on the initiation and progression of ALS and effects on ALS associated protein (SOD1, TDP-43) expression and aggregation. In addition, the effect of the inhibition of protein aggregation by thioflavin T (ThT), a compound that has been shown to bind protein fibrils and slow aggregation will be studied.