Environmental risk factors linked to TDP-43 proteinopathies

ABSTRACT Most neurodegenerative diseases are sporadic with unknown etiology that likely stems from the interaction between genetics and the environment, the latter of which continues to remain poorly understood. Epidemiological studies have linked environmental exposures to the development of TDP-43 pathology, widely considered a hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) but has now been expanded to a host of other age-related neurodegenerative disorders including Alzheimer's disease (AD) (collectively referred to as TDP-43 proteinopathies). To begin addressing some of the major gaps in our understanding of how environmental risk factors are linked to neurodegeneration, we performed a high-content microscopy screen to identify environmental toxicants that mediate TDP-43 dysfunction and identified pathology “promoters” that have never been linked to TDP-43 or dementia, thus opening the possibility that we can 1) uncover new risk factors that impact the onset or progression of neurodegeneration, 2) identify the cellular pathways and disease contexts through which they operate, and 3) provide a new paradigm for therapeutic interventions that are based on environmental susceptibility. We assembled a team of experts covering TDP-43 pathogenesis, genetic modeling, high-content screening, and computational modeling to address our overarching hypothesis that distinct classes of at-risk environmental toxicants drive TDP- 43 dysfunction, neurodegeneration, and memory & motor decline. To address this hypothesis, we will evaluate a high priority subset of environmental toxicants identified in our screen based on their prevalence and levels of human exposure. In Aim-1, we will examine the pathophysiological relevance of toxicant exposure using in vivo and neuronal models that allow us to interrogate their functional impact. In Aim-2, we will evaluate exactly how toxicants mediate TDP-43 dysfunction and will examine direct cysteine-dependent and indirect stress-responsive mechanisms that would link environmental toxicants to enhanced TDP-43 aggregation. In Aim-3, we will evaluate the extent to which toxicants affect TDP-43-dependent pathways vs. global disruption of other key FTD/ALS-associated signaling pathways. This study is innovative because it is the first systematic survey of at-risk chemicals affecting TDP-43, enabling us for the first time to connect environmental agents to neurodegenerative disease. Our study is also significant because it could radically transform our understanding of how an environmental agent may drive or perhaps increase susceptibility to disease, which could logically inform strategies to alleviate or mitigate disease burden.