title: Organophosphate neurotoxicity to the voluntary motor system on the trail of environment-caused amyotrophic lateral sclerosis: the known, the misknown, and the unknown.
abstract: Amyotrophic lateral sclerosis (ALS) is the most common adult-onset paralytic disorder. It is characterized by progressive degeneration of the motor neurons controlling voluntary movement. The underlying mechanisms remain elusive, a fact that has precluded development of effective treatments. ALS presents as a sporadic condition 90-95% of the time, i.e., without familial history or obvious genetic mutation. This suggests that ALS has a strong environmental component. Organophosphates (OPs) are prime candidate neurotoxicants in the etiology of ALS, as exposure to OPs was linked to higher ALS incidence among farmers, soccer players, and Gulf War veterans. In addition, polymorphisms in paraoxonase 1, an enzyme that detoxifies OPs, may increase individual vulnerability both to OP poisoning and to the risk of developing ALS. Furthermore, exposure to high doses of OPs can give rise to OP-induced delayed neuropathy (OPIDN), a debilitating condition akin to ALS characterized by similar motor impairment and paralysis. The question we pose in this review is: "what can we learn from acute exposure to high doses of neurotoxicants (OPIDN) that could help our understanding of chronic diseases resulting from potentially decades of silent exposure (ALS)?" The resemblances between OPIDN and ALS are striking at the clinical, etiological, neuropathological, cellular, and potentially molecular levels. Here, we critically present available evidence, discuss current limitations, and posit future research. In the search for the environmental origin of ALS, OPIDN offers an exciting trail to follow, which can hopefully lead to the development of novel strategies to prevent and cure these dreadful disorders.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.|NIEHS Center for Environmental Health Sciences in Northern Manhattan, Columbia University, New York, NY, 10032, USA.|Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, 10032, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Merwin
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.|NIEHS Center for Environmental Health Sciences in Northern Manhattan, Columbia University, New York, NY, 10032, USA.|Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, 10032, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Obis
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.|NIEHS Center for Environmental Health Sciences in Northern Manhattan, Columbia University, New York, NY, 10032, USA.|Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, 10032, USA.|Toxicology Ph.D. Program, Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.
authors.forename: Yanelli
authors.initials: Y
authors.lastname: Nunez
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA. dr2240@cumc.columbia.edu.|NIEHS Center for Environmental Health Sciences in Northern Manhattan, Columbia University, New York, NY, 10032, USA. dr2240@cumc.columbia.edu.|Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, 10032, USA. dr2240@cumc.columbia.edu.|, 722 W 168th street Suite 1107B, New York, NY, 10032, USA. dr2240@cumc.columbia.edu.
authors.forename: Diane B
authors.identifier: http://orcid.org/0000-0002-6842-6759
authors.initials: DB
authors.lastname: Re
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology; D000818:Animals; D004781:Environmental Exposure / Q000009:adverse effects; D006801:Humans; D015994:Incidence; D020258:Neurotoxicity Syndromes / Q000503:physiopathology*; D010755:Organophosphates / Q000633:toxicity*
chemical_list: D010755:Organophosphates
keywords: Amyotrophic lateral sclerosis; Delayed neuropathy; Motor neuron; Neurodegeneration; Neurotoxicity; Organophosphate