Biology Reference
In-Depth Information
counterparts to
-synuclein
,
ATP13A2
, and
FBXO7
. Nevertheless, while it is
early days for
ATP13A2
and
FBXO7
, the dominant, toxic gain-of-function
mechanism by which
-synuclein is thought to act in DA neuron death supports
the use of a transgenic approach using the human
-synuclein
gene to study the
-synuclein pathogenesis in Drosophila (see below). The existence of Drosophi-
la homologs of most of the genes implicated in heritable forms of PD implies that
the pathways regulated by these genes are also likely to be conserved in
Drosophila.
A. Advantages and limitations of Drosophila to model PD
The widespread use and tractability of Drosophila have spurred the development
and refinement of a versatile and powerful array of molecular and genetic tools.
Both mutational and transgenic approaches have been used to create and study
the Drosophila models of neurological disease. The mutational approach involves
the generation of mutations in Drosophila counterparts of human disease genes,
whereas the transgenic approach involves the introduction and expression of a
human disease gene in Drosophila. The former approach is typically used when
the corresponding human disease results from a loss-of-function mutation in a
particular gene, whereas the latter approach is more often used when the
corresponding human disease appears to result from a dominant toxic gain-of-
function mechanism. However, a combination of both techniques is typically
employed for a full and thorough genetic analysis of the functional role of an
endogenous gene of interest. This section outlines some of the typical methodol-
ogies involved in the modeling approaches discussed throughout.
1. Mutagenesis and related loss-of-function techniques
There are a number of different techniques that can be employed to generate
mutations in a particular Drosophila gene of interest. Many of the classical
methods for recovering mutations in defined genes in Drosophila require a
predictable phenotype that can be readily identified, such as developmental
defects or preadult lethality. However, there are now a number of methods
available that allow the recovery of mutations in defined genes irrespective of
the mutant phenotype. One particularly powerful approach involves the use of
transposable elements. A number of specifically engineered transposons have
been designed that can be used for insertional mutagenesis in Drosophila. These
transposons are being utilized by a large consortium, for example, the Berkeley
Drosophila Genome Project, in an effort to generate mutations in most Drosoph-
ila genes as a service to the Drosophila research community. Primarily as a result
of these efforts, it is currently estimated that more than 50% of the predicted
