Environmental Toxins and Parkinson’s Disease: An Open Issue

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by rigidity, resting tremor, and bradykinesia. It is produced by the selective loss of dopaminergic neurons within the substantia nigra pars compacta (SN). PD affects millions people worldwide being the second most common age-related neurodegenerative disorder with a prevalence of 1900 per 100,000 in people over 80 years and 41 per 100,000 in people around 40 50 years of age. Symptoms may appear when about 80% of dopaminergic cells are lost although neurodegeneration might start decades before the onset of motor symptoms. The etiology of PD and the exact cause of dopaminergic cell loss are unknown. At least 15 genes have been associated with PD but genetic causes are responsible for a minority of cases. Instead, epidemiologic studies associate the risk of PD with exposure to environmental toxicants such as pesticides, herbicides, solvents, metals, and pollutants. Additional risk factors are drugs, brain trauma and cerebrovascular damage. The first causal relationship between toxins and PD started in 1982 when it was discovered that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Figure 1), present as a contaminant in a synthetic drug, caused idiopathic PD in drug abusers [1]. Afterward, extensive research has characterized MPTP as a selective neurotoxin inducing most of the biochemical, pathological, and behavioral features of PD, but not all (e.g. absence of Lewy bodies of α-synuclein aggregates). MPTP crosses the blood-brain barrier and is metabolized (activated) by MAO-B to an intermediate that is ultimately converted to 1-methyl-4-phenylpyridinium cation (MPP+). MPP+ is selectively transported into dopaminergic neurons by dopamine transporter (DAT). MPP+ concentrates into mitochondria and inhibits Complex I. These events result in mitochondrial dysfunction and dopaminergic cell death by apoptosis leading to dopamine depletion and Parkinsonism. Relevant aspects are: toxicity is produced by a metabolite of MPTP, activation to pyridinium cation is essential for neurotoxicity and is blocked by MAO-B inhibitors, and selectivity depends on the selective uptake of MPP+ by dopaminergic cells through DAT.