Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease

Parkinson's disease (PD), the most frequent movement disorder, is Caused by the progressive loss of the dopamine neurons within the substantia nigra pars compacta (SNc) and the associated deficiency of the neurotransmitter dopamine in the striatum. Most cases of PD Occur sporadically With unknown Cause, hot Mutations in several genes have been linked to genetic forms of PD (alpha-synuclein, Parkin, DJ-1, PINK1, and LRRK2). These genes have provided exciting new avenues to study PD pathogenesis and the mechanisms underlying the selective dopaminergic neuron death in PD. Epidemiological studies in humans, as well as molecular studies in toxin-induced and genetic animal models of PD show that mitochondrial dysfunction is a defect Occurring early in the pathogenesis of both sporadic and familial PD. Mitochondrial dynamics (fission, fusion, migration) is important for neurotransmission, synaptic maintenance and neuronal survival. Recent studies have shown that PINK1 and Parkin play crucial roles in the regulation of mitochondrial dynamics and function. Mutations in DJ-1 and Parkin render animals more susceptible to oxidative stress and mitochondrial toxins implicated in sporadic PD, lending support to the hypothesis that some PD cases may be caused by gene-environmental factor interactions. A small proportion of alpha-synuclein is imported into mitochondria, where it accumulates in the brains of PD patients and may impair respiratory complex 1 activity. Accumulation of clonal, somatic mitochondrial DNA deletions has been observed in the substantia nigra during aging and in PD, suggesting that mitochondrial DNA mutations in some instances may predispose to dopamine neuron death by impairing respiration. Besides compromising cellular energy production, mitochondrial dysfunction is associated with the generation of oxidative stress, and dysfunctional mitochondria more readily mediate the induction of apoptosis, especially in the face of cellular stress. Collectively, the Studies examined and summarized here reveal an important causal role for mitochondrial dysfunction in PD pathogenesis, and suggest that drugs and genetic approaches with the ability to modulate mitochondrial dynamics, function and biogenesis may have important clinical applications in the future treatment of PD. (C) 2009 Elsevier Inc. All rights reserved.