%0 Journal Article
%T Genetic Mutations and Mitochondrial Toxins Shed New Light on the Pathogenesis of Parkinson's Disease
%A Shigeto Sato
%A Nobutaka Hattori
%J Parkinson's Disease
%D 2011
%I Hindawi Publishing Corporation
%R 10.4061/2011/979231
%X The cellular abnormalities in Parkinson's disease (PD) include mitochondrial dysfunction and oxidative damage, which are probably induced by both genetic predisposition and environmental factors. Mitochondrial dysfunction has long been implicated in the pathogenesis of PD. The recent discovery of genes associated with the etiology of familial PD has emphasized the role of mitochondrial dysfunction in PD. The discovery and increasing knowledge of the function of PINK1 and parkin, which are associated with the mitochondria, have also enhanced the understanding of cellular functions. The PINK1-parkin pathway is associated with quality control of the mitochondria, as determined in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization. To date, the use of mitochondrial toxins, for example, 1-methyl-4-phynyl-tetrahydropyridine (MPTP) and CCCP, has contributed to our understanding of PD. We review how these toxins and familial PD gene products are associated with and have enhanced our understanding of the role of mitochondrial dysfunction in PD. 1. Introduction ParkinsonĄ¯s disease (PD) is the most common neurodegenerative movement disorder, affecting 1% of the population above the age of 60. The classical form of the disease is characterized clinically by rigidity, resting tremor, bradykinesia, and postural instability. In addition to these four cardinal symptoms, many nonmotor symptoms frequently appear in PD, such as cognitive impairment, hallucinations, delusion, behavioral abnormalities, depression, disturbances of sleep and wakefulness, loss of smell, pain, and autonomic dysfunctions such as constipation, hypotension, urinary frequency, impotence, and sweating. The pathological hallmarks of PD are the preferential loss of dopaminergic neurons of the substantia nigra (SN) pars compacta and formation of Lewy bodies. Exposure to environmental factors inducing mitochondrial toxin like1-methyl-4-phynyl-tetrahydropyridine (MPTP) produces selective degeneration of dopaminergic neurons in SN and results in an irreversible Parkinsonism [1¨C3]. The active metabolite of MPTP, 1-methyl-4-phenylpyridinium ion (MPP+), is an inhibitor of complex I, and it accumulates in dopaminergic neurons because it is actively transported via dopamine transporter (DAT) [4¨C6]. The inhibition of the electron transport induces oxidative damage by increasing the formation of reactive oxygen species (ROS) and leads to further mitochondrial dysfunction [7]. These findings were supported by evidence
%U http://www.hindawi.com/journals/pd/2011/979231/