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(Cha
et al.
,2005;Greene
et al.
,2003). The inability of previous work to detect
neuron loss in
mutants is likely explained by technical limitations of the
approaches used, as discussed above, and the simple fact that most of these studies
focused exclusively on the PPM1/2 cluster (Cha
parkin
et al.
, 2005; Pesah
et al.
,2004;Yang
et al.
,2003) owing to the reported effects of
-synuclein expression on this cluster.
mutants is associated with a dramatic and
widespread apoptotic degeneration of muscle tissue, and the male sterility derives
from a late defect in spermatid formation. Ultrastructural studies revealed that
profound loss of mitochondrial integrity was the earliest manifestation during
muscle degeneration and also apparent in spermatids, suggesting a role for parkin
in mitochondrial integrity (Greene
The motor deficit of
parkin
et al.
, 2003). While humans and mice with
parkin
mutations do not appear to manifest similar muscle and germline pheno-
types, mitochondrial defects are a common characteristic of sporadic PD and a
conserved feature in all organisms with
parkin
mutations, including humans
(Flinn
et al.
, 2009; Mortiboys
et al.
, 2008; Muftuoglu
et al.
, 2004; Palacino
et al.
, 2005). These observations provide compelling evidence
that parkin may act to regulate mitochondrial integrity and that mitochondrial
dysfunction is an important contributing factor to DA neuron death in patients
with mutated parkin function. Moreover, our finding that Drosophila
, 2004; Ved
et al.
parkin
mutants exhibit DA neuron loss further suggests that the pathogenic mechan-
isms responsible for neurodegeneration under these circumstances are conserved
and hence tractable by analysis of the Drosophila models.
B. DJ-1
Drosophila has also proven useful in dissecting the role of the
DJ-1
gene. Similar
to
, a small protein of unclear function
with homology to proteases, kinases, and small heat shock proteins, result in
Parkinsonism in humans (Bonifati
parkin
, loss-of-function mutations in
DJ-1
et al.
, 2003). The Drosophila genome encodes
two homologs of the human
DJ-1
gene, designated
DJ-1
and
DJ-1
(Table 1.1).
The
DJ-1
gene appears to be ubiquitously expressed, whereas
DJ-1
expression
is largely, or exclusively, restricted to testes (Menzies
et al.
, 2005; Meulener
et al.
,
2005; Park
,we
and others have used traditional genetics and RNAi to perturb the functions of
these genes (Lavara-Culebras and Paricio, 2007; Menzies
et al.
, 2005). To explore the biological roles of
DJ-1
and
DJ-1
et al.
, 2005; Meulener
et al.
, 2005; Park
, 2005).
The results of studies involving traditional mutant alleles of the
et al.
, 2005; Yang
et al.
DJ-1
genes indicate that flies lacking one or both of the
genes are fully viable,
fertile, and display no evidence of DA neuron loss. However, further studies of
these mutants revealed that
DJ-1
double
mutants display a striking sensitivity to particular stress-inducing agents, includ-
ing paraquat and rotenone—chemicals which have been epidemiologically
DJ-1
single mutants and
DJ-1;DJ-1
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