Impact of Environmental Risk Factors on Mitochondrial Dysfunction, Neuroinflammation, Protein Misfolding, and Oxidative Stress in the Etiopathogenesis of Parkinson’s Disease

Abstract

As a prevalent progressive neurodegenerative disorder, Parkinson’s disease (PD) is characterized by the neuropathological hallmark of the loss of nigrostriatal dopaminergic (DAergic) innervation and the appearance of Lewy bodies with aggregated α-synuclein. Although several familial forms of PD have been reported to be associated with several gene variants, most cases in nature are sporadic, triggered by a complex interplay of genetic and environmental risk factors. Numerous epidemiological studies during the past two decades have shown positive associations between PD and several environmental factors, including exposure to neurotoxic pesticides/herbicides and heavy metals as well as traumatic brain injury. Other environmental factors that have been implicated as potential risk factors for PD include industrial chemicals, wood pulp mills, farming, well-water consumption, and rural residence. In this review, we summarize the environmental toxicology of PD with the focus on the elaboration of chemical toxicity and the underlying pathogenic mechanisms associated with exposure to several neurotoxic chemicals, specifically 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat (PQ), dichloro-diphenyl-trichloroethane (DDT), dieldrin, manganese (Mn), and vanadium (V). Our overview of the current findings from cellular, animal, and human studies of PD provides information for possible intervention strategies aimed at halting the initiation and exacerbation of environmentally linked PD.

Relative Molecular Similarity in Compound Structures Modulating Neurodegenerative Apoptosis

“…Neuroprotective compounds superimpose over the cyclised ring; fitting points are frequently cyclised ring atoms including O8, with bulky chemical groups ad-jacent to the ring structure. Several neurotoxic pesticides have been linked to the development of Parkinson's through initiating mitochondrial dysfunction [59] and all compounds in Figure 1 Of the simple neurotoxin compounds used in animal models to induce dopaminergic neurodegeneration, MPTP initiates a high proportion of Parkinsonian symptoms [26]. Figure 4 demonstrates that the molecular structures of compounds providing protection against MPTP do not compete for the same template fitting-points; only astilbin has 2 common fitting-points with MPTP.…”

Cannabidiol Protects Dopaminergic-like Neurons against Paraquat- and Maneb-Induced Cell Death through Safeguarding DJ-1CYS106 and Caspase 3 Independently of Cannabinoid Receptors: Relevance in Parkinson’s Disease

“…Therefore, protection of DAergic neurons against deleterious insults and avoidance of neuronal cell death have become an ultimate goal in medicinal research. 5,6 Although, the etiopathogenesis of the disease is still ill defined, several data suggest that exposure to environmental neurotoxicants such as pesticide paraquat (PQ 2+ ) and maneb (MB) 7,8 and genetic susceptibility (e.g., DJ-1 gene 9 ) play an important causative role in mitochondrial dysfunction, protein misfolding, and oxidative stress (OS). In line with this, Mathas and co-workers have recently shown that PQ 2+ and MB inhibited the esterase activity of DJ-1, a critical cellular antioxidant and signaling protein, 10−12 by 20 ± 4 and 100 ± 6%, respectively.…”

The Molecular Basis for the Environmental Promotion of Neurodegenerative Disease

“…The review by Huang et al [ 2 ] addresses the neurotoxic agents that appear to promote the prevalence of Parkinson’s disease. In addition to pesticides and several heavy metals, traumatic brain injury increases the risk of incurring this disorder.…”