Biology Reference
In-Depth Information
proteins. Using a genetic approach, Trinh and colleagues found that attenuation
of the Drosophila
, ablated the protective effects of coffee and
tobacco. These findings support the need to investigate further the potential for
manipulation of Nrf2 as a therapeutic approach, especially through the action of
bioactive compounds such as those found in coffee and tobacco.
The general role of oxidative stress and potential of antioxidant
approaches is evident from multiple additional studies using transgenic lines,
expressing Cu/Zn superoxide dismutase or methionine sulfoxide reductase, and
small-molecule antioxidants such as glutathione,
Nrf2
homolog,
Cnc
-acet-
ylcysteine, ascorbic acid, and various other antioxidants, all having positive
effects in
S
-methyl
L
-cysteine,
N
-synuclein
,
parkin
, and
DJ-1
models (Botella
et al.
, 2008; Faust
et al.
,
2009; Park
, 2007). The therapeutic
potential is further extended to sporadic models by the positive effects of various
polyphenol antioxidants against paraquat-induced neurotoxicity (Jimenez-Del-
Rio
et al.
, 2007; Saini
et al.
, 2010; Wassef
et al.
, 2010). One potential source of oxidative stress, also suggested to be a
contributing to environmental risk factor, is the chemical reaction catalyzed by
heavy metals (iron, copper, and manganese) known as the Fenton chemistry.
This reaction results in the conversion of relatively labile hydrogen peroxide to
the much more potent hydroxyl radicals. Unsurprisingly,
et al.
mutants are
highly sensitive to Fe and Cu exposure; conversely, the administration of metal
chelating agents significantly improved lifespan of
parkin
,
2010). In contrast, it was also reported that uptake of dietary Zn markedly
improved
parkin
mutants (Saini
et al.
phenotypes (Saini and Schaffner, 2010). The reasons for this
are currently unclear but are thought to be independent from the Fenton
chemistry and may be due to antioxidant properties of Zn.
While all these findings add further weight to the magnitude of evidence
that oxidative stress has a contributing role to play in the pathogenesis of PD,
the general lack of evidence that antioxidant therapies so far attempted
provide any benefit is disappointing. These previous approaches may be ham-
pered by technical difficulties, not only least in delivering small-molecule thera-
peutics across the blood-brain barrier but they also fail to shed light on a key area
of consideration for PD and almost all neurodegenerative disorders, that of cell
type specificity—what makes DA neurons particularly susceptible? While it
should be immediately cautioned that nigral DA neurons are prominently
affected in PD, it is certainly true that other neuronal types eventually succumb
to disease. So the problem is not simply a matter of DA specificity, although this
is an obvious culprit to probe. Indeed, an unavoidable linkage to our old
adversary, oxidative stress, is provoked by the well-recognized fact that the
normal metabolism of DA produces ROS and dopa-quinone conjugates
(Hattori
parkin
, 2009). Hence, a number of groups have utilized the tractability
of the Drosophila models to address the contribution of DA to selective neuronal
vulnerability.
et al.
