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Conversely, HDAC6 overexpression ameliorated
-synuclein retinal disruption,
but suppression of DA neurodegeneration was not reported in this study. Inter-
estingly, HDAC6 overexpression did cause a decrease in the amount of soluble
-synuclein oligomers correlating with neuroprotection, consistent with previ-
ously discussed mechanisms of chaperone-mediated protection. Finally, another
valuable link should be noted here since HDAC6 has been implicated in
the autophagic removal of protein aggregates and dysfunctional organelles.
Hence, this mechanism may also have relevance to the PINK1/parkin-induced
mitochondrial dysfunction.
In summary, as we learn more about the pathogenic mechanism(s) under-
lying the disease more putative therapeutic interventions will come to light. With-
out doubt the biggest advantage that the Drosophila models can bring to the field is
genetic analyses that reveal new insights into the pathogenic mechanism and
potentially protective pathways. Our current understanding would indicate that
there is no single pathogenic insult decreasing the likelihood of a single “magic
bullet” disease-modifying therapy. More likely, such an intervention will need to
consider multiple toxic events. However, the findings discussed here have already
highlighted a few key regulators of important protective mechanisms. One could
envisage a combined approach to activate the production of protective factors such
as chaperone, antioxidant, and phase II detoxifying enzymes, perhaps throughNrf2-
or 4E-BP-mediated mechanisms, alongside damage removal processes by stimula-
tion of autophagy. In any case, the availability and validity of Drosophila models for
PD provide an excellent opportunity for early stage drug testing to reduce the cost
and risk associated with developing such a therapeutic, prior to further testing in
mammalian preclinical models.
VII. CONCLUSIONS
The fruit fly
has proven itself to be an invaluable model system in
basic studies of genetics and biology for over 100 years. Given the remarkable
degree of genetic, molecular, and cell biological conservation between flies and
mammals that has been revealed over the decades, Drosophila remains a valid
model system in which to address novel biological questions in the future,
including those relevant to human health. Indeed, work aimed at an understand-
ing of the genes involved in heritable forms of PD has already made significant
contributions to our understanding of the causes of this debilitating disease.
Moreover, these studies have begun to define small-molecule compounds that
could potentially impinge on the pathways implicated in PD. Drosophila models
also lend themselves directly to unbiased high-throughput screening of small-
molecule libraries in the search for better compounds that are able to combat
pathogenesis.
D. melanogaster
