Mapping the ALS Exposome to Gain New Insights into Disease Risk and Pathogenesis

摘要

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with complex un- known pathogenesis. Recent evidence supports a gene-time-environment hypothesis whereby environmental exposures trigger neurodegeneration when superimposed on a genetic risk profile. Supporting this premise, long-term adverse environmental exposures are linked to ALS risk and progression; we have shown that measured and reported pesticide exposures strongly increase ALS risk and that high levels of persistent or- ganic pollutants (POPs) decrease ALS survival in ALS subjects in Michigan. Therefore, there is a need to de- lineate the “ALS exposome,” defined as the lifetime of environmental exposures that contributes to ALS risk. In this proposal, our objectives are to improve our ALS exposome model by enhancing insight into pollutant mix- tures associated with ALS accounting for genetic risk, identifying periods of susceptibility to exposures, corre- lating toxin measurements in easily assessable biofluids with epidemiologic data, and identifying whether these environmental toxins are absorbed into the central nervous system (CNS) in order to improve insight into the gene-time-environment hypothesis in ALS. Our central hypothesis is that identifying environmental pollutants in biofluids and CNS tissues will advance models of ALS pathogenesis. In Aim 1, we will better characterize the ALS exposome by measuring environmental toxins in biological samples obtained longitudinally from ALS sub- jects from the University of Michigan ALS Patient Repository and age- and sex-matched controls across the State of Michigan to yield insight into the pollutant mixtures that contribute to disease risk and survival, ac- counting for genetic susceptibility via polygenic risk scores. In Aim 2, we will evaluate residential and occupa- tional histories for association with ALS risk and survival, while also correlating exposure histories to toxin measures from Aim 1, to gain comprehensive insight into exposure mixtures and time windows critical for ALS risk. Finally, in Aim 3, we will quantitate environmental toxins and heavy metals in ALS and control CNS tis- sues, and link peripheral alterations with observed changes in ALS CNS tissue and critical exposure windows to thereby ascertain environmental risk factors that potentially contribute to ALS pathogenesis. Overall, suc- cessful completion of these aims will have an important positive translational impact by identifying ALS disease risk factors associated with occupational and environmental exposures, while accounting for genetic suscepti- bility. This proposal will therefore expand our understanding of the ALS exposome in the context of genetic risk, identify toxins that pose a public health risk, identify occupations linked to exposures, and establish a framework to test for these exposures in other neurodegenerative diseases. This understanding of the ALS exposome will support much-needed public health interventions to target modifiable disease risk factors in this lethal disorder.