Etiology of Parkinson's disease: Genetics and environment revisited.

Abstract

Idiopathic Parkinson's disease (PD) is the second most common neurodegenerative disorder and affects more than 1 million Americans over the age of 55. The disease selectively affects dopaminergic neurons of the substantia nigra pars compacta, culminating in their demise. After ≈50% of the dopamine neurons and 75–80% of striatal dopamine is lost, patients start to exhibit the classical symptoms of PD including bradykinesia, postural reflex impairment, resting tremor, and rigidity (1, 2). Although there are several treatments that are effective for a number of years, their usefulness wanes over time and is accompanied by unacceptable side effects. New therapies are clearly needed for this disorder. Despite many years of focused research, the causes of this disease remain to be elucidated. Understanding the cause of PD is critical as that knowledge could lead to directed research that will develop new and potent therapies. The relative contributions of genetic versus environmental factors regarding the cause of PD have been hotly debated. In an attempt to define a cause for this disease, early epidemiological studies examining twins suggested an absence of genetic factors (3). However, these studies were not definitive and could never account for differences in disease progression between twin pairs that could account for discordance in diagnosis. The discovery that the protoxin n -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in both humans and nonhumans further strengthened the hypothesis that PD had an environmental etiology. Other environmental toxins have been shown to induce a parkinsonian state as well, supporting this view (4). However, the recent discovery of inherited forms of PD shifted the emphasis back to genetic factors. Among the different genetic forms of PD, mutations in the gene encoding for α-synuclein have received the most attention. Mutations in this gene cause rare forms of PD. Furthermore, α-synuclein is also present in the …