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.

6-Shogaol, an active compound of ginger, protects dopaminergic neurons in Parkinson's disease models via anti-neuroinflammation

“…When MPP + accumulates in dopaminergic neurons in the SNpc, it inhibits complex I of the mitochondrial electron transport chain, ultimately leading to toxic injury and dopaminergic cell degeneration [14] . The loss of dopaminergic neurons is associated with the onset of motor deficits in which there is a direct relationship between the extent of dopamine loss and motor dysfunction [15] . The present study showed that 6-shogaol treatment significantly improved MPTP-induced motor deficits and bradykinesia in pole test.…”

“…Furthermore, these cytokines may stimulate the expression of [24] . This process may lead to the production of toxic amounts of NO free radicals, which in turn could potentiate the expression and release of TNF-α by adjacent microglial cells and thereby further amplify the inflammatory reaction [15,25] . The accumulation of these factors is thought to contribute to neuronal damage, particularly in PD [26,27] .…”

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

“…The etiology of PD remains unknown, although ∼5% of cases are linked with monogenetic inheritance and involve genetic mutations in at least six genes (SNCA, LRRK2, PARK2, PINK1, DJ-1, and ATP13A2) (3). For the remaining 95% of cases, strong epidemiological evidence associating the exposure with a variety of environmental agents, especially pesticides, has been suggested (4)(5)(6). Agents that cause formation of reactive oxygen species through mitochondrial inhibition, disruption of dopamine handling, or redox cycling, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat, and rotenone, all cause dopaminergic toxicity in animal models (7).…”

Aluminum Intoxication through Leaching in Food Preparation

“…Many researches revealed the neurological effects of Al ions on human health such as Alzheimer disease (Perl and Brody, 1980;Walton, 2006), other adverse consequences like Dialysis Encephalopathy (Shaw et al 2008;Tomljenovic, 2013), and Amyotrophic Horizontal Sclerosis Höglinger, 2008, Tomljenovic, 2011) (Table 1). Patients for Alzheimer's disease, Parkinson disease and dialysis encephalopathy have high Aluminum concentrations in their brain tissues ( Soni et al, 2001;Tabrizi, 2007).…”