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...

(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.