Biology Reference
In-Depth Information
1. Transgenic models
Consistent with the significant interest in LRRK2 pathobiology in the field, a
number of groups have independently generated and characterized transgenic
lines expressing WT and mutated forms of human LRRK2. However, so far the
reported observations do not show a clear or consistent pattern of observations
despite a variety of mutated forms being investigated, including G2019S, I2020T,
I1915T, Y1699C, R1441C, Y1383C, I1122V, and G2385R (see Table 1.2).
For instance, Ng
observed late stage degeneration of DA neurons
(PPM1/2 and PPM3 only) with G2019S, Y1699C, and G2385R, and essentially
no retinal degeneration, with no effects from WT LRRK2 (Ng
et al.
et al.
, 2009);
however, Liu
reported that expression of both WT and G2019S caused
retinal degeneration and progressive loss of DA neurons in all clusters (Liu
et al.
,
2008). While it may be argued that the toxic effects of WT LRRK2 observed by
Liu
et al.
suggest that deregulation of LRRK2 can trigger pathogenesis, it is hard
to be confident at this stage in light of negative results of essentially the same
experiment, especially since a lack of effect by WT LRRK2 was also reported by
Imai
et al.
(2008). In this study, they also observed late stage selective DA
neuron loss caused by I1915T and Y1385C but this time in the PPM1/2 and
PPL1 clusters. However, Venderova
et al.
report a rather confusing pattern of
sensitivity under different conditions. They saw significant but rather variable
effects of WT, I1122V, Y1699C and I2020T on DA neurons (PPM1/2 and PPL1
only) under basal conditions but all clusters seemed to be sensitive upon rote-
none exposure (Venderova
et al.
, 2009). While they observed modest effects on
locomotion and survival, dramatic disruption of eye tissue was reported; howev-
er, these experiments were conducted at 29
C which as noted below can
confound analysis of eye morphology.
The discrepancies are hard to reconcile; however, experimental varia-
tions, especially the use of different GAL4 drivers, are commonly invoked. In
these situations, neuronal expression has been differentially achieved by the use
of
et al.
-GAL4 lines which, coupled with the effect of each unique
insertion site genomic structure, quite likely induce expression at subtly different
levels. In contrast, the studies appear to commonly use
elav
-,
ddc
-, and
TH
-GAL4 to drive eye-
specific expression, but it is well appreciated in the field that different
GMR
-
GAL4 lines exist which induce expression at varying levels and high GAL4
levels can themselves be toxic (Kramer and Staveley, 2003).
At present, all of these observations await independent replication,
which is undoubtedly facilitated by the sharing of unique reagents including
transgenic lines for which the Drosophila community is well known. With the
expectation of more independently derived lines to be forthcoming, a clearer
picture of the cellular effects of WT and mutated LRRK2 can be anticipated.
Indeed, it would be interesting to compare the effects of all transgenic lines under
GMR
