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protein in membrane and vesicular dynamics (Tofaris and Spillantini, 2007).
Although mutations of the
-synuclein gene (A53T, A30P, E46K, duplication,
and triplication; see Gasser, 2009) appear to be an extremely rare cause of PD,
the perceived importance of
-synuclein in the pathobiology of PD was signifi-
cantly increased with the discovery that
-synuclein is a component of the Lewy
body inclusions in sporadic PD patients and has a propensity to self-aggregate
(Conway
et al.
, 1998; Spillantini
et al.
, 1997). Thus, investigations into the
mechanism by which
-synuclein induces neuronal loss could lead to the
development of treatment strategies impacting on multiple forms of PD.
While most of the human genes that have been implicated in PD have
Drosophila counterparts (Table 1.1), there appears to be no Drosophila ortholog
of the
-synuclein gene. However, because both missense mutations and
increased dosage of the
-synuclein gene confer dominant forms of Parkinsonism
(Bennett, 2005; Eriksen
et al.
, 2005), transgenic flies expressing WT or mutated
human
-synuclein under the transcriptional control of a GAL4-responsive
UAS element were generated to assess the contribution of
-synuclein to PD
pathogenesis. The main salient features that one might anticipate, and certainly
that warrant investigation, are selective DA neuron degeneration, the presence
of proteinaceous Lewy body-like inclusions, locomotor deficits, and perhaps early
death. In addition, to capitalize on the potential to exploit a Drosophila model
for genetic screening, it would be advantageous to observe an easily scorable
phenotype such as that described for polyglutamine disease models; progressive
degeneration of eye tissue (Fernandez-Funez
et al.
, 2000; Warrick
et al.
, 1998).
-synuclein-expressing transgenic lines have been
independently generated and characterized. To investigate the effects of
To date, a number of
-
synuclein on disease-relevant features, these lines have been crossed to a variety
of tissue-specific GAL4 lines and the effects of
-synuclein expression have been
assessed on DA neurons, the entire nervous system, and eye tissue. Remarkably,
initial reports indicated that
-synuclein-expressing flies recapitulate all the
major features of PD stimulating intense interest in this model. Initial studies
reported that pan-neuronal expression of
-synuclein led to a near complete and
relatively selective degeneration of DA neurons (the PPM1/2 clusters were
primarily studied), a concomitant decline in climbing ability, the accumulation
of proteinaceous inclusions, and progressive degeneration of retinal tissue (Feany
and Bender, 2000). Intriguingly, similar effects were observed with the expres-
sion of either WT or the A30P and A53T mutated
-synuclein, suggesting that
simply mis-regulated
-synuclein abundance may drive toxicity.
However, while these initial observations have largely been corrobo-
rated by recent reports from the same group (Chen and Feany, 2005; Chen
,
2009), there have been considerable inconsistent effects reported by other
groups, raising some questions about the “genuine” effects of transgenic
et al.
-
synuclein expression. Other groups using independently derived equivalent
