In vivo models of LRRK2

Many laboratories interested in developing models of PD have used LRRK2 overexpression in various organisms as a way to understand how mutations in this protein might cause PD. Simultaneously, this work will help validate or exclude
LRRK2 as a potential therapeutic target. The LRRK2 gene is highly conserved through evolution, although in many invertebrates, deciding whether the orthologue more closely resembles human LRRK1 or LRRK2 becomes challenging. Overexpression of the Drosophila orthologue of the human LRRK genes (dLRRK) appears well tolerated by Drosophila cells, and loss of the orthologue results in defects in dopaminergic
neurons, although this result has not recapitulated in other strains of flies. Expression of human WT or G2019S-LRRK2 in Drosophila results in cellular toxicity in both photoreceptor cells and dopaminergic neurons. Overexpression of dLRRK containing missense mutations in areas of the protein homologous to PD-associated mutations in the human LRRK2 gene causes significant loss of TH-positive cells, whereas expression of wild-type dLRRK or dLRRK2 with mutations predicted to inactivate kinase activity does not cause similar phenotypes. The initial studies in Drosophila suggest that LRRK2, particularly LRRK2 kinase activity, is a
valid target important for neurodegeneration. The identification of PD-causative mutations in the a-syn gene more than 10 years ago led to the description of transgenic mice overexpressing human a-syn*2.5 years later. The last 10 years witnessed numerous dramatic and impressive advances in transgenic technologies. However, since LRRK2 mutations in PD cases were described, transgenic
rodents with phenotype have yet to be described in the literature some 4 years later. Problems with cloning and manipulating LRRK2 constructs in combination with downstream expression issues seem to plague the field and may prevent fundamental questions regarding LRRK2 and neurodegeneration from being addressed in a timely fashion. Once the technical issues are resolved, rodent transgenic models may provide a springboard toward identifying and validating not only LRRK2 as a target for disease but also validating potential therapies as they arise to mitigate pathogenic processes.