ABSTRACT
One of the most widely held hypotheses concerning the etiology of idiopathic Parkinson’s disease (IPD) is the socalled “two-hit” model, which links genetic and environmental factors. Underlying this model are the facts that familial association of the disease was noted early in the previous century (the genetic influence), and there is a higher prevalence of the disease in industrialized Western societies than is seen in less developed ones (the neurotoxicant exposure). A major boost to the hypothesis came from the recognition of the effects of the protoxin, 1methyl-4-phenyl-1, 2, 3, 6tetrahydropyridine (MPTP), which in vivo is converted to the selective dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+). This chemical causes a condition that is clinically indistinguishable from IPD.1,2 Discovery of the mutation in the αsynuclein gene that gives rise to the A30P variant protein demonstrated for the first time that genetic polymorphism could be the causal defect in familial PD.3 Unfortunately, none of the genetic loci subsequently identified with other forms of familial PD4-13 has been shown to be a major factor in the etiology of IPD. Although mutations in the parkin gene were found in a small minority of IPD patients, the latest evidence suggests that there is no association of this gene with IPD.14
