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developmental compensation to loss of
DJ-1
in null animals relative to the acute
loss of
activity in RNAi treated animals later in development, or to an
unexpected off-target effect of the
DJ-1
RNAi constructs. While off-target effect
of RNAi is a well-recognized phenomenon, it is tricky to predict but relatively
trivial to exclude. The availability of genomic tools for other Drosophila species,
as described above, should allow definitive phenotypic rescue by expression of an
RNAi-resistant ortholog. Nevertheless, it is difficult to envision how perturbation
of a gene that is predominantly or exclusively expressed in the male germline
could result in loss of viability and neuronal degeneration.
Regardless of the explanations for the discordant results of studies of the
Drosophila
DJ-1
gene family, all of these studies support the increasing body of
evidence linking DJ-1 to the oxidative stress response pathway. A number of
studies have demonstrated that human DJ-1 is modified upon oxidative stress by
sulfonification of cysteine residues. Importantly, mutational analysis of con-
served cysteine residues in Drosophila DJ-1
DJ-1
revealed that modification at
C104 (analogous to C106 in human DJ-1) is critical for the antioxidant protec-
tive function of DJ-1
, 2006). Interestingly, this modifica-
tion increases with age in Drosophila and human tissues (Meulener
in vivo
(Meulener
et al.
, 2006);
nevertheless, DJ-1 double mutants display an age-dependent decline in mito-
chondrial function (Hao
et al.
, 2010). An important challenge of future work will
be to discern between the myriad biological functions ascribed to this protein
family to define the mechanism by which loss of DJ-1 function protects against
neuron loss, but it seems most likely that the major contribution of DJ-1 is in the
response to oxidative stress to maintain mitochondrial integrity. In support of
this, an interesting recent study found that feeding
et al.
mutant flies various
dietary antioxidants, including vitamin C, melatonin, and vitamin E, was able to
significantly extend lifespan of these mutants (Lavara-Culebras
DJ-1
et al.
, 2010),
hinting at a potential therapeutic benefit of antioxidants.
C. PINK1
Mutations in
, which encodes a putative protein kinase, are a rare cause
of recessive Parkinsonism, but has provided some significant insights into
possible pathogenic mechanisms. The presence of a putative mitochondrial
targeting sequence in PINK1 coupled with its predominant localization to
mitochondria (Silvestri
PINK1
et al.
, 2005; Valente
et al.
, 2004) strongly suggested that
loss-of-function mutations in
somehow compromise mitochondrial in-
tegrity. This prediction is born out in three studies that simultaneously described
the effects of perturbation of a Drosophila homolog of
PINK1
PINK1
(Clark
et al.
, 2006;
Park
et al.
, 2006; Yang
et al.
, 2006). Two papers show that null mutations of the
Drosophila
ortholog result in degeneration of indirect flight muscles
and defective spermatid formation (Clark
PINK1
et al.
, 2006; Park
et al.
, 2006).
