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importantly their genetic reduction was also sufficient to suppress DA neuron
loss by pathogenic LRRK2. Interestingly, biochemical analyses revealed that
hLRRK2/dLRRK physically interacted with hAgo2/dAgo1 which also bound
4E-BP. The strength of this interaction appeared to increase with mutant
LRRK2 which correlated with 4E-BP hyperphosphorylation, but this mechanism
remains to be proven. It was hypothesized that this increased interaction would
aberrantly relieve the miRNA translational repression. Consistent with this
nonphosphorylatable 4E-BP antagonized the inhibition of let-7 by mutant
LRRK2. Since 4E-BP itself plays an important role in regulating protein transla-
tion, it will be interesting to determine whether the downstream effects of
pathogenic LRRK2 on protein translation are mediated principally via miRNA
regulation or through the direct action of 4E-BP on the protein translation
machinery. Nevertheless, together, these findings have highlighted regulated
protein translation as a therapeutic avenue to explore further.
IV. RECESSIVE TRAITS
In contrast to the dominant toxic gain-of-function of
-synuclein and LRRK2
mutations, at least three of the genes associated with heritable forms of PD clearly
involve loss-of-function mutations (Table 1.1). A precise understanding of the
normal biological functions of the corresponding genes and the pathways regu-
lated by these genes will be invaluable in uncovering the mechanisms by which
these mutations cause PD. One of the most powerful approaches to address these
issues involves the use of classical genetic analysis in a simple model organism
such as Drosophila to explore the biological functions of evolutionarily conserved
homologs of these genes. This approach has recently been used to analyze the
biological functions of Drosophila
parkin
,
DJ-1
, and
PINK1
homologs.
A. Parkin
To explore the biological role of parkin, we and others generated a series of
mutations in the Drosophila ortholog of
parkin
, including deletion, nonsense, and
missense mutations. Flies lacking the
gene are semi-viable and display
reduced longevity, DA neuron degeneration, motor deficits, and male sterility
(Greene
parkin
et al.
, 2003; Pesah
et al.
, 2004; Whitworth
et al.
,2005). Although initial
studies of Drosophila
mutants failed to detect DA neuron loss, subsequent
analysis using whole-mount confocal analysis indicates that a subset of DA neurons
restricted to the PPL1 cluster do indeed degenerate in
parkin
parkin
mutants, while seroto-
nergic neurons remain intact (Whitworth
et al.
,2005). In addition to the degenera-
tion of neurons in the PPL1 cluster,
mutants also manifest reduced TH
staining in the PPM1/2 cluster and significantly reduced DA content in the brain
parkin
