Biology Reference
In-Depth Information
Similar to vertebrate
LRRK2
,
dLRRK
appears to be broadly expressed
(Lee
, 2007) which does not reveal any secrets as to its function but does
suggest a common cellular role. A couple of mutant alleles have so far been
described but the most reliably informative is an insertion of a piggyBac transpo-
son element which resides between exons 5 and 6,
et al.
dLRRK
e03680
. This insertion
causes exon 6 to be mis-spliced (Wang
, 2008); however, it is still conceiv-
able that a small proportion is correctly spliced and so homozygotes may not
represent a complete genetic null.
Homozygous
et al.
mutants are viable to adult stage with a normal
lifespan and overall appear grossly normal if a little smaller than WT animals.
Several studies are in agreement that the loss of
dLRRK
has no effect on survival
of DA neurons, but mild locomotor deficits have been measured (Lee
dLRRK
et al.
, 2007;
Tain
, 2009b). However, variable effects have been noted upon exposure to
oxidative stressors; Wang
et al.
et al.
observed a slight sensitivity to hydrogen peroxide,
while Imai
et al.
reported a noticeable resistance to the same toxin (Imai
et al.
,
2008; Wang
, 2008). Precise experimental conditions and genetic back-
ground easily vary under these tests, which would warrant careful controlling
before meaningful interpretation.
One intriguing and unexpected phenotype was observed; while mutant
males are fully fertile, females have severely reduced fecundity. While the exact
basis of this defect is currently unknown, Drosophila oogenesis is an intensely
studied system, thus, this phenotype offers an attractive opportunity to tap this
knowledge and investigate the function of dLRRK. Furthermore, it may also
provide a model system for experimental manipulation, for example, to test
genetic interaction of putative functional partners.
et al.
3. Mechanistic insights from LRRK2 models
To date, relatively few studies on the Drosophila models have extended beyond
initial characterization, but significantly the most intriguing is the report of a
novel putative target of LRRK2 kinase activity. Following a speculative previous
link between the PI3K/Akt/TOR signaling pathway and other fly models, Imai
et al.
(2008) demonstrated genetic interactions between dLRRK and several
components of this pathway. Candidate testing revealed that dLRRK showed
some potential kinase activity toward 4E-BP, a negative regulator of the eIF4E
protein translation machinery. 4E-BP is known to be negatively regulated by
phosphorylation via the TOR signaling pathway, and its activity is important
for survival under a wide variety of stresses including starvation, oxidative stress,
unfolded protein stress, and immune challenge (Bernal and Kimbrell, 2000;
Kapahi
, 2005). Consistent
with this, genetic analyses showed that loss of 4E-BP exacerbated toxicity of
et al.
, 2004; Teleman
et al.
, 2005; Tettweiler
et al.
