Glial-Neuronal Interactions during Oxidative Stress: Implications for Parkinson's Disease

Abstract

Idiopathic Parkinson’s disease (PD) is a common neurological disorder of adult onset (estimated prevalence 1:1000 of the population), with tremor, rigidity, bradykinesia, and postural instability as the primary symptoms. The etiology of PD is not known. The majority of the cases are sporadic although inherited parkinsonism is reported in several families. Recently, it was discovered that a mutation in the α-synuclein gene (A53T) is associated with autosomal dominant PD in several families (1,2). There is also evidence suggesting a systemic defect in mitochondrial respiration in PD (3–7), possibly transmitted through the mitochondrial genome (8). This defect results in decreased activity of complex I of the mitochondrial respiratory chain (3) and links idiopathic and l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism (9). MPTP causes degeneration of dopamine neurons through its metabolism by monoamine oxidase B (MAO B) to the neurotoxin l-methyl-4-phenylpyridine (MPP+), which inhibits complex I activity (10). Other environmental factors may also influence the risk for PD (11–13). Endogenous neurotoxins, such as products of dopamine catabolism and/or isoquinolines, are also thought to potentially contribute to the pathogenesis of PD (14,15). Neuropathologically PD is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, with consequent severe reductions in the dopamine content of the striatum (16). Other areas of the brain (norepinephrine neurons in the locus ceruleus, cholinergic neurons in the nucleus basalis of Mynert) are also affected in PD, but to a lesser degree. The cause of the selective degeneration of dopamine neurons in PD is not understood at present. Several theories have been proposed to explain this selective loss. Data obtained from postmortem studies, as well as in vivo and in vitro experiments support a role of oxidative stress in the selective degeneration of dopamine neurons in PD.