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linked to PD (Lavara-Culebras and Paricio, 2007; Meulener
et al.
, 2005; Park
et al.
, 2005). This sensitivity is unique to chemical agents that induce oxidative
stress and is not manifest by chemical agents that induce other types of cellular
stress
implicated in PD,
including ER stress and proteasome inhibition
(Meulener
, 2005). Moreover, treatment of WT flies with these oxidative
stress-inducing chemical agents results in a modification of DJ-1
et al.
protein elec-
trophoretic mobility that can be detected by Western blot analysis or isoelectric
focusing, suggesting that DJ-1
is a direct target of an oxidative modification as
has been seen with vertebrate DJ-1.
mutants manifest no apparent sensi-
tivity to these same oxidative stress-inducing agents, although transgenic expres-
sion of either DJ-1
DJ-1
or DJ-1
is able to rescue the chemical sensitivity of
DJ-1
single mutants and
double mutants.
In contrast to these findings, work by Menzies
DJ-1;DJ-1
et al.
, using independent-
ly generated alleles of the
gene, found that these mutants exhibit delayed
age-dependent reduction of TH staining in the central nervous system and were
less sensitive to paraquat exposure than to WT flies (Menzies
DJ-1
, 2005). The
authors ascribe these two phenotypes to a compensatory induction of
et al.
DJ-1
expression in response to loss of
function, and provide expression and
transgenic data in support of this model. Even more surprisingly, two studies of
the
DJ-1
DJ-1
gene (Lavara-Culebras and Paricio, 2007; Yang
et al.
, 2005) found that
strong ubiquitous knockdown of the
DJ-1
transcript with RNAi resulted in
larval lethality (Yang
, 2005), while partial knockdown dramatically re-
duced lifespan (Lavara-Culebras and Paricio, 2007). These results clearly con-
trast with previous finding that
et al.
null mutants are fully viable and exhibit
no apparent phenotype, and should be interpreted with caution. Moreover, these
investigators found that targeted knockdown of
DJ-1
expression in the com-
pound eye results in photoreceptor cell loss, and that knockdown of
DJ-1
DJ-1
expression in the nervous system results in the progressive loss of TH-positive
neurons in the PPM1/2 cluster (documented using the paraffin sectioning/light
microscopy methodology) and reduced DA content in fly heads.
While overall the studies of the Drosophila
gene family reached
similar conclusions, a disconcerting feature of this work involves the stark pheno-
typic differences reported in the individual studies. Although further work will be
required to explain these discrepancies, there are several likely sources. One
potential source of the discordant results is methodological. In particular, while
some studies (Lavara-Culebras and Paricio, 2007; Meulener
DJ-1
et al.
, 2005; Park
et al.
,
2005) made use of definitive null alleles of the Drosophila
DJ-1
gene family, the
alleles used by Menzies
may well be hypomorphic in nature, and other work
involved RNAi techniques (Menzies
et al.
, 2005). The more
severe phenotypes resulting from RNAi-mediated knockdown of
et al.
, 2005; Yang
et al.
DJ-1
activity
relative to null alleles of
cannot be readily explained by a hypomorphic
effect of RNAi. These conflicting results are better explained by a possible
DJ-1
