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Another application of Drosophila models of PD is to use these models
in genomic studies to identify pathways involved in pathogenesis. A recent
genomic study of the
-synuclein transgenic fly model identified 51 Drosophila
transcripts that displayed an altered abundance relative to control flies (Scherzer
et al.
, 2003). Importantly, these transcripts were unaffected in transgenic flies
expressing the neurodegeneration-inducing tau protein, indicating that the
abundance of these 51 transcripts is specifically altered in response to
-synu-
clein expression. The 51 transcripts that display altered abundance in the
-
synuclein transgenic flies encode proteins involved in lipid metabolism, energy
production, and membrane transport, potentially implicating these pathways in
-synuclein pathogen-
esis in yeast identified lipid metabolism and vesicle transport components as a
major category of genetic modifiers of
-synuclein pathogenesis. Interestingly, a recent study of
,
2003). Together, these two studies suggest an evolutionarily conserved pathway
of PD pathogenesis involving lipid metabolic and vesicle trafficking defects.
Additional work will be required to validate the functional significance of
these pathways to DA neuron degeneration.
-synuclein toxicity (Willingham
et al.
B. LRRK2
The relatively high prevalence of LRRK2 mutations in familial as well as in
sporadic cases has provoked significant interest in developing various model
systems to investigate the function and dysfunction of LRRK2, including in
Drosophila. Although mutations in LRRK2 are inherited in a dominant manner
which can be replicated by transgenic expression, it is relevant and informative to
gain insight into the normal function by studying loss-of-function or knockout
scenarios. Consequently, a number of groups have reported on a variety of models
characterizing the effects of manipulating LRRK2 and its Drosophila homolog.
LRRK2
encodes a large, complex, multidomain protein, comprising 2527
amino acids protein (
280 kDa) which contains leucine-rich repeat (LRR), Ras
of complex (ROC), C terminal of ROC (COR), putative serine/threonine kinase
and GTPase domains, and several WD40 protein-protein interactions domains.
More than 20 different mutations in LRRK2 have been linked to autosomal
dominant Parkinsonism and the G2019S mutation has been shown a high preva-
lence in sporadic cases particularly in certain genetically isolated communities.
A number of groups have shown that G2019S may confer an increase in native
kinase activity, and an apparent increase in toxicity. However, not all mutations
act likewise; I2020T causes decrease in kinase activity, while the other mutations
cause a propensity to aggregate. Thus, mutation of LRRK2 has the potential to
cause a multitude of pathogenic effects. Furthermore, the normal physiological
function(s) of LRRK2 currently remain poorly understood.
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