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negative findings in mammalian systems (Vives-Bauza
, 2010). Although
the molecular mechanism of their relationship remains to be elucidated, the
epistatic hierarchy established in Drosophila has since been validated in mam-
malian cells showing human
et al.
parkin
can suppress mitochondrial phenotypes
caused by loss of
PINK1
(Dagda
et al.
, 2009; Exner
et al.
, 2007). Clinical reports
that
mutations confer similar symptoms in humans adds
support that these cases may be caused by a common pathogenic mechanism
(Zadikoff
PINK1
and
parkin
-
mediated Parkinsonism, the absence of Lewy body inclusions, is not shared in
common with
et al.
, 2006). Surprisingly however, a distinctive feature of
parkin
affected patients, as a recent report describes the presence
of Lewy bodies on the first analyzed postmortem sample (Samaranch
PINK1
, 2010).
Although the current consensus supports PINK1 and parkin acting in a common
pathway to maintain mitochondrial integrity (discussed more below), the precise
mechanisms by which their dysfunction leads to neuronal death are unclear and
may indeed cause different pleiotropic effects at the end stage of pathology.
et al.
D. Omi/HtrA2
High-temperature requirement A2 (HtrA2/Omi) is a mitochondrial protease that
exhibits proapoptotic and cell protective properties and has been linked to PD. Two
mutant alleles of
(A141S and G399S) have been found in PD patients,
leading to the classification of
HtrA2
,2005).
Although one of these genetic variants was later found in non-PD controls (Ross
et al.
HtrA2
as
PARK13
by OMIM (Strauss
et al.
(2008) identified a
new mutation (Arg404) in a large cohort of Belgian PD patients, confirming a role
for HtrA2 in PD susceptibility. Importantly, recent studies have shown that HtrA2
forms a complex with PINK1 (Plun-Favreau
, 2008; Simon-Sanchez and Singleton, 2008), Bogaerts
et al.
,2007). Moreover, HtrA2 is
phosphorylated in a PINK1-dependent manner in response to p38 SAPK (stress-
activated protein kinase) pathway activation, suggesting that PINK1 can modulate
HtrA2 activity as part of mitochondrial stress response.
To date, only two studies have so far described the characterization of
independently derived mutant alleles of Drosophila
et al.
HtrA2/Omi
(Tain
et al.
,
2009a; Yun
et al.
, 2008). One study isolated a small deletion removing
HtrA2
(Tain
, 2009a), while the other identified two chemically induced muta-
tions, a nonsense mutation causing and early truncation and a substitution of
conserved V110E (Yun
et al.
et al.
, 2008). Phenotypic analysis of these mutants
revealed that
is required for male fertility, normal lifespan, and stress
resistance but not for maintenance of DA neuron. In addition, only very mild
mitochondrial defects were quantified in one study (Tain
HtrA2
et al.
, 2009a) but not
qualitatively noted in the other V110E allele (Yun
, 2008). Interestingly,
Drosophila HtrA2 has also been reported to be released from the mitochondria
upon cellular insults such as UV irradiation, and to cleave DIAP1, the principal
et al.
