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11-20-2011, 05:00 PM | #1 | |||
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http://www.springerlink.com/content/458v700477303k30/
Parkin, PINK1 and mitochondrial integrity: emerging concepts of mitochondrial dysfunction in Parkinson’s disease Anna Pilsl and Konstanze F. Winklhofer . A major breakthrough in PD research was the identification of monogenetic variants, which account for up to 10% of all PD cases. So far, six genes have conclusively been linked to PD (reviewed in [56, 105, 122, 149]). Autosomal-dominant parkinsonism is caused by mutations in the genes encoding a-synuclein or LRRK2 (leucine-rich repeat kinase 2, dardarin), whereas mutations in the genes encoding parkin, PINK1 (PTEN-induced kinase 1), DJ-1, or ATP13A2 lead to autosomal-recessive parkinsonism (Fig. 1). Recent insight into the function and dysfunction of PD-associated genes has reinforced the notion that mitochondrial dysfunction plays a crucial role in PD. First evidence for a possible link between mitochondria and PD was provided in the late 1970s/early 1980s when young drug addicts in the United States developed acute and irreversible parkinsonism after intravenously using a meperidine analog which was contaminated by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [28, 88]. MPTP crosses the blood–brain barrier, is oxidized to the toxic species MPP in glial cells, and can then be taken up by dopaminergic neurons via the dopamine transporter [68, 104]. In dopaminergic neurons MPP has been shown to inhibit complex I activity of the mitochondrial electron transport chain, resulting in a decrease in oxidative phosphorylation, and an increase in the generation of reactive oxygen and nitrogen species [17, 121, 133]. Prompted by insights into the molecular action of MPTP, complex I activities were analyzed in tissues from PD patients. Indeed, in post-mortem SNc samples from PD patients complex I activities were found to be reduced [141], whereas data from peripheral tissue, such as blood cells or skeletal muscle, are less consistent (reviewed in [14 The interest in mitochondrial alterations linked to PD tremendously increased when it became evident that some PD-associated gene products have a direct or indirect impact on mitochondrial integrity (reviewed in [1, 7, 10, 11, 59, 103, 140, 170, 171, 181]). The most compelling link between PD genes and mitochondria has emerged from studies on PINK1 and parkin; we, therefore, concentrate on mitochondrial effects mediated by these proteins in the following sections...
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