Mechanisms Underlying Long-Latency Neurodegenerative Diseases of Environmental Origin

Abstract

Sporadic neurodegenerative diseases comprise a majority of cases of amyotrophic lateral sclerosis (sALS), Parkinson disease (sPD), and Alzheimer disease (sAD), the causes of which are presumably environmental factors acting alone or in concert with genetic susceptibilities. Identification of culpable exogenous agents is challenging because years/decades may intervene between critical exposures and clinical appearance of neurodegenerative disease. Epidemiological studies can help identify risk factors, but detailed assessment of exposomes (from conception to disease onset) is needed to identify potential toxicants, the culpability of which, and underlying mechanisms thereof, are assessed in the experimental laboratory. Research on young persons who develop brain disease is a useful strategy because the exposure period is manageable, parents are available to describe exposures in utero and during infancy and, if the degree of exposure correlates inversely with disease latency, there is a greater chance of identifying culpable agents. While far from complete, this approach is illustrated by a prototypical neurodegenerative disease of established environmental origin that combines ALS with atypical parkinsonism (P) and AD-like dementia (D). Known as the Western Pacific ALS/PD Complex (ALS/PDC), intensive field and laboratory study has identified etiologic roles for phytochemicals that target DNA during development and throughout adult life. Studies of ALS/PDC, and of parkinsonism/sPD associated with exposure to the organophosphate dichlorvos, have revealed common genotoxic mechanisms that trigger neuronal degeneration. Lessons learned from these studies can be used in the field and laboratory to discover other environmental risk factors associated with sPD, sALS, and sAD.