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...