Genetics of Parkinson's disease and parkinsonism
ABSTRACT Until 10 years ago, conventional wisdom held that Parkinson's disease was not a genetic disorder. Since that time, there have been a plethora of genetic findings, culminating in the cloning of several genes that derive from the loci given the nomenclature PARK1-PARK12 (OMIM 168600). Recently, these research findings have begun to impact clinical practice, and this impact is likely to increase. The primary purpose of this article is to outline these genetic advances, discuss their importance for current practice in clinical and related settings, and outline briefly how they are influencing research into the causes of and possible future treatments for this prevalent disorder.
Frontiers in Bioscience 01/2008; 13(13):718. DOI:10.2741/2714 · 4.25 Impact Factor
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ABSTRACT: The parkin gene has been shown to be genetically altered in a wide variety of human tumors including lung cancer. Although many parkin splice variants have been identified, to date, most of the studies have only been focused on originally cloned isoforms. In this work, for the first time, the expression profile of parkin isoforms in human lung adenocarcinomas has been analyzed to identify their involvement in lung cancer. Their contribution in some biological conditions, such as proteasomal degradation or mitophagy or cell death, has been analyzed in human lung cells. The expression profile of parkin isoforms has been investigated in paraffin-embedded samples of human lung adenocarcinomas by using Western blot analysis. Their expression has also been evaluated in human lung adenocarcinoma and in human normal bronchial epithelial cell lines following treatment with a proteasome inhibitor or mitochondrial depolarizing agent, or in serum starvation. Parkin proteins were detected on blot by using two antibodies, AbI and AbII, which recognize different domains of originally cloned parkin. Furthermore, parkin immunolocalization has been visualized in both cell lines by using immunofluorescence analysis. Results have shown that H1 and/or H5, H14, H4 and/or H8 and/or H17 and H3 and/or H12 isoforms are expressed in human lung adenocarcinomas. Some of them are also present in A549 cell line, whereas they are absent or faintly expressed in BEAS-2B cells. Furthermore, their expression changed after treatment. Human lung adenocarcinomas express different parkin isoforms, which might represent markers of malignancy and could be linked to specific biological functions.Tumor Biology 02/2015; DOI:10.1007/s13277-015-3166-z · 2.84 Impact Factor
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ABSTRACT: The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with l-DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and l-DOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson's disease. Copyright © 2014 Elsevier Inc. All rights reserved.Neurobiology of Disease 10/2014; 74C:66-75. DOI:10.1016/j.nbd.2014.10.016 · 5.20 Impact Factor