Neurodegenerative diseases: neurotoxins as sufficient etiologic agents?

Abstract

A dominant paradigm in neurological disease research is that the primary etiological factors for diseases such as Alzheimer's (AD), Parkinson's (PD), and amyotrophic lateral sclerosis (ALS) are genetic. Opposed to this perspective are the clear observations from epidemiology that purely genetic casual factors account for a relatively small fraction of all cases. Many who support a genetic etiology for neurological disease take the view that while the percentages may be relatively small, these numbers will rise in the future with the inevitable discoveries of additional genetic mutations. The follow up argument is that even if the last is not true, the events triggered by the aberrant genes identified so far will be shown to impact the same neuronal cell death pathways as those activated by environmental factors that trigger most sporadic disease cases. In this article we present a countervailing view that environmental neurotoxins may be the sole sufficient factor in at least three neurological disease clusters. For each, neurotoxins have been isolated and characterized that, at least in animal models, faithfully reproduce each disorder without the need for genetic co-factors. Based on these data, we will propose a set of principles that would enable any potential toxin to be evaluated as an etiological factor in a given neurodegenerative disease. Finally, we will attempt to put environmental toxins into the context of possible genetically-determined susceptibility.

Fig. 1

Schematic representation of different modes of putative gene-environment interactions in the etiology of a neurodegenerative disease ‘‘X’’, as defined by a unique clinical or neuropathological phenotype. (a) One of several genetic mutations may be the sole trigger the disease. (b) One of several environmental toxins may be the sole trigger of the disease. (c) One or several genetic mutations may be the prime trigger of the disease, the penetrance or severity of which may be modified by environmental factors. (d) One or several environmental toxins may be the prime trigger of the disease, the penetrance or severity of which may be modified by genetic factors. (e) Environmental and genetic factors, both being too weak individually to trigger the disease, may be required, interacting in a synergistic manner to trigger the disease