Biology Reference
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genetic screen for modifiers of
phenotypes which identified a number of
factors that influence the partial lethality of
parkin
parkin
mutants including genes
involved in the oxidative stress pathway (Greene
et al.
, 2005). The most potent
enhancer of the
parkin
partial lethal phenotype was a loss-of-function allele of
the
) gene. Furthermore, subsequent work
found that transgenic overexpression of GstS1 was able to significantly suppress
the loss of DA neurons in
glutathione S-transferase S1
(
GstS1
, 2005).
The GST family of polypeptides is thought to act in cellular detoxifica-
tion pathways and by regulating the cellular redox balance in a number of ways,
such as covalently coupling GSH to a variety of products of oxidative damage,
including 4-hydroxynonenol, or by maintaining the correct redox state of pro-
tein thiol groups (Hayes
parkin
mutants (Whitworth
et al.
, 2005). The interest in GSTs as a potential
therapeutic is significantly elevated with the recognition that there are several
dietary components and drugs that are able to induce the expression of glutathi-
one
et al.
, 2003). In an
interesting development to this finding, the protective effects of GSTS1 have
also been demonstrated against
S
-transferase and GSH production in vertebrates (Nguyen
et al.
, 2008).
Furthermore, the therapeutic potential of chemical inducers of GSTs was
demonstrated with the administration of allyl disulfide and sulforaphane,
which are known to induce phase II detoxifying enzymes, were able to potently
suppress
-synuclein toxicity (Trinh
et al.
, 2008).
In another exciting development, Pallanck's group has also begun to
reveal the mechanisms behind the previously recognized association of coffee
and tobacco use with decreased risk of PD. Epidemiological studies have
provided some remarkable evidence that drinking coffee or smoking tobacco
can reduce the incidence of PD but the reasons have been unclear. One hypoth-
esis has proposed that caffeine and nicotine may confer symptomatic relief;
alternatively, coffee and tobacco may contain neuroprotective agents (Quik
et al.
-synuclein-induced DA neurodegeneration (Trinh
et al.
, 2008; Schwarzschild
et al.
, 2006). To address these hypotheses directly,
Trinh
mutant
lines, and revealed that feeding these flies extracts of tobacco and coffee was able
to potently suppress age-dependent DA neuron loss (Trinh
et al.
used two models of PD, the transgenic
-synuclein
and
parkin
, 2010), mirror-
ing the epidemiological findings. Furthermore, they showed that caffeine and
nicotine did not contribute to the neuroprotective effects, suggesting the “regu-
lar” coffee and tobacco contains some chemical(s) that actively promotes neu-
roprotective mechanisms. Interestingly, coffee and tobacco also appear to
provide protection in diverse neurodegenerative models including Alzheimer's
and polyglutamine disease, implicating the induction of a general neuroprotec-
tive program. To understand the underlying mechanism, the Keap-Nrf2 pathway
was assessed as a likely candidate. Nrf2 is a transcription factor that under normal
conditions is sequestered in the cytoplasm by Keap1, however, upon oxidative
stress Keap1 releases Nrf2 which can drive transcription of cytoprotective
et al.
