Expression of the full-length human wild type LRRK2 protein using the bacterial artificial chromosome (BAC).
Endogenous LRRK2: yes
Corresponding human genotype: LRRK2 is the greatest known genetic contributor to Parkinson’s disease.
Targeted gene: LRRK2
Overall transgene expression is about 3.5 fold higher than the endogenous LRRK2 in the brain of the transgenic animals (although it is much higher in the hippocampus: 20 fold). Anatomical expression patterns are similar to the endogenous mouse gene but the level of the protein is increased.
22-24 months: No differences are detected in the number of TH-positive cells in the SN.
18 months: In vivo striatal levels of DA are significantly lower in transgenic animals compared to control littermates at baseline (striatal microdialysis). No differences are observed after amphetamine injection Note that no differences in the level of DA or its metabolites (DOPAC, HVA) are observed in the striatum of the transgenic mice post-mortem (HPLC). A modest increase in the number of striatal dopamine D1 (significant) and D2 (non-significant) receptors density is observed.
up to 24 months: No abnormalities can be seen with alpha-synuclein, phosphorylated alpha-synuclein or phosphorylated tau staining.
22-24 months: No significant changes are observed during motor assessments (open field, beam crossing test, inked footprint analysis, negative geotaxis test).
Response to dopaminergic treatment
18 months: No differences are observed the DA/metabolites striatal ratio changes and stored DA induced by treatment with the D2 receptor antagonist raclopride.
18-24 months: No visible changes are observed in activated microglia (Iba-1 immunostaining).