FAQ/Help |
Calendar |
Search |
Today's Posts |
11-20-2011, 05:00 PM | #1 | |||
|
||||
Senior Member
|
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...
__________________
In the last analysis, we see only what we are ready to see, what we have been taught to see. We eliminate and ignore everything that is not a part of our prejudices. ~ Jean-Martin Charcot The future is already here — it's just not very evenly distributed. William Gibson |
|||
Reply With Quote |
04-13-2012, 08:47 AM | #2 | |||
|
||||
Senior Member
|
(this is on an open access site--full text available)
Leucine-rich repeat kinase 2 and alpha-synuclein: intersecting pathways in the pathogenesis of Parkinson's disease? Elisa Greggio, Marco Bisaglia, Laura Civiero and Luigi Bubacco* The electronic version of this article is the complete one and can be found online at: http://www.molecularneurodegeneration.com/content/6/1/6 Abstract Although Parkinson's disease (PD) is generally a sporadic neurological disorder, the discovery of monogenic, hereditable forms of the disease has been crucial in delineating the molecular pathways that lead to this pathology. Genes responsible for familial PD can be ascribed to two categories based both on their mode of inheritance and their suggested biological function. Mutations in parkin, PINK1 and DJ-1 cause of recessive Parkinsonism, with a variable pathology often lacking the characteristic Lewy bodies (LBs) in the surviving neurons. Intriguingly, recent findings highlight a converging role of all these genes in mitochondria function, suggesting a common molecular pathway for recessive Parkinsonism. Mutations in a second group of genes, encoding alpha-synuclein (α-syn) and LRRK2, are transmitted in a dominant fashion and generally lead to LB pathology, with α-syn being the major component of these proteinaceous aggregates. In experimental systems, overexpression of mutant proteins is toxic, as predicted for dominant mutations, but the normal function of both proteins is still elusive. The fact that α-syn is heavily phosphorylated in LBs and that LRRK2 is a protein kinase, suggests that a link, not necessarily direct, exists between the two. What are the experimental data supporting a common molecular pathway for dominant PD genes? Do α-syn and LRRK2 target common molecules? Does LRRK2 act upstream of α-syn? In this review we will try to address these of questions based on the recent findings available in the literature.
__________________
In the last analysis, we see only what we are ready to see, what we have been taught to see. We eliminate and ignore everything that is not a part of our prejudices. ~ Jean-Martin Charcot The future is already here — it's just not very evenly distributed. William Gibson |
|||
Reply With Quote |
Reply |
|
|
Similar Threads | ||||
Thread | Forum | |||
Link Mitochondrial Dysfunction and alpha-Synuclein Multiplication | Parkinson's Disease | |||
mitochondrial dysfunction in complex diseases | Parkinson's Disease | |||
early onset PD with Parkin compared with early onset PD without Parkin | Parkinson's Disease | |||
mitochondrial dysfunction and faulty cellular alarm | Parkinson's Disease | |||
Thread integrity.. | Community & Forum Feedback |