Biology Reference
In-Depth Information
Overall, such a mechanism is attractive for several reasons: first, it offers
an explanation for the variety of mitochondrial defects that have been docu-
mented in PINK1 and parkin-deficient cell lines, including decreased membrane
potential, deficits in the electron transport chain complexes, reduced ATP
synthesis, decreased mitochondrial DNA synthesis, and aberrant mitochondrial
calcium efflux (Gandhi
, 2009)by
suggesting that these pleiotropic phenotypes derive from the accumulation of
damaged mitochondria in the absence of a functional mitochondrial quality
control system. Second, these findings would explain the protective effects of
PINK1 and parkin overexpression from exposure to mitochondrial toxins
(Haque
et al.
, 2009; Gegg
et al.
, 2009; Morais
et al.
, 2006); and finally, the
abundant mitochondrial DNA mutational load of substantia nigra DA neurons
(Bender
et al.
, 2008; Paterna
et al.
, 2007; Rosen
et al.
, 2006) would neatly account for the
selective vulnerability of this population of cells to the loss of a mitochondrial
quality control system. While many of the details of the mechanism still remain
to be resolved, it is clear that significant advances have been made in our
understanding of how the PINK1/parkin pathway promotes neuronal longevity.
et al.
, 2006; Kraytsberg
et al.
VI. CONVERGENT THERAPEUTIC APPROACHES
A vast amount of evidence links many neurodegenerative diseases with some
contribution, direct or secondary, from oxidative stress (Sayre
, 2008). This
situation is not entirely surprising since a natural and unavoidable consequence
of oxygen metabolism is the production of potentially damaging ROS. These
molecules can chemically modify, and presumably damage, all manner of cellular
components including protein, lipid, DNA, and so on. A host of complex and
normally robust mechanisms exists to combat or repair ROS-mediated oxidative
damage; however, the effect of compromised antioxidant defenses is most obvi-
ously threatening to highly energy-demanding, postmitotic tissues such as the
nervous system. Here again, Drosophila models offer a unique advantage to
modeling this process
et al.
since adult flies are composed almost entirely of
postmitotic tissues, with the exception of germ cells and some intestinal tissues,
thus avoiding the technical limitations of needing to focus solely on the nervous
system. As a result, much effort has been invested in studying the role of
oxidative stress in the pathogenesis of PD and methods to combat it using the
Drosophila models.
All of the models to date have exhibited, to a greater or lesser degree,
some sensitivity to oxidative stress, typically induced via either exposure to high
levels or oxygen or oxidative chemicals such as hydrogen peroxide or paraquat.
This has primed the field to rapidly address the relative efficacy of transgenic or
pharmacologic antioxidant mechanisms. One of the earliest leads came from a
in vivo
