Biology Reference
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transgenic dLRRK, while its overexpression, in particular expression of a consti-
tutively active form, was sufficient to prevent DA neuron loss (Imai
, 2008).
These findings suggest that LRRK2 may normally regulate the activity of 4E-BP,
in a similar manner to TOR but in response to an unknown signal, and that
mutated LRRK2 may aberrantly inactivate 4E-BP. This would prevent 4E-BP
from regulating protein translation and inhibit its effects in promoting cellular
survival.
et al.
Presently, it is unclear how specific or robust the direct phosphorylation
of 4E-BP by dLRRK is, as data for other candidate proteins were not shown.
Others have even suggested that human LRRK2 may have a poor affinity for 4E-
BP1 (Kumar
, 2010), so further work on this is warranted. Nevertheless, the
potential importance of 4E-BP and regulated protein translation has attracted
much attention recently due to a number of supportive findings. First, a genetic
screen independently identified 4E-BP as a genetic interactor in an unrelated fly
model of PD,
et al.
, 2005), and subsequently
my group demonstrated that genetic or pharmacologic activation of 4E-BP was
sufficient to prevent neurodegeneration (Tain
parkin
mutants (see below; Greene
et al.
, 2009b). Second, additional
links to aberrant protein translation are emerging from reports that indicate
mutations in
et al.
EIF4G1
, encoding part of the translation machinery, have been
identified as a new
locus causing dominant inherited PD. The inability of
a cell to make an appropriate response to environmental changes by altering its
proteomic profile would render it susceptible to increased toxic insults. Further-
more, recent work has demonstrated that 4E-BP mediates its protective effects, at
least in part, by the preferential increase in production of numerous mitochon-
drial proteins (Zid
PARK
, 2009). The growing emphasis on mitochondrial dys-
function and oxidative stress as a key contributor to PD makes this an attractive
therapeutic mechanism. In addition, the modulation of mutant
et al.
pheno-
types by 4E-BP suggests that dLRRK, and perhaps LRRK2, toxicity may be partly
due to mitochondrial dysfunction.
A very recent study has provided some potentially very interesting
novel insights into the LRRK2-mediated pathogenic mechanism, which again
points toward dysregulation of protein production. A number of tentative links
had previously been made between PD and the microRNA pathway—small
noncoding RNAs that bind to transcript 3
0
-untranslated regions to regulate
translation. Gehrke and colleagues identified several intriguing genetic interac-
tions between transgenic dLRRK I1915T or hLRRK2 G2019S and components
of the RNA-induced silencing complex (RISC),
dLRRK
, and also two
miRNAs, let-7 and miR-184*, such that antagonizing these factors enhanced the
pathogenicity of mutant LRRK2 (Gehrke
ago1
and
dicer1
, 2010). In turn, these miRs were
shown to regulate the translation of two transcriptional regulators,
et al.
,
respectively. Consistently, these transcripts were regulated by LRRK2 activity,
overexpressed by pathogenic LRRK2, and downregulated in
e2f1
and
dp
LRRK
mutants, but
