Expression of the full-length human mutant (R1441C) LRRK2 protein, HA-tagged, under the control of a CMV enhancer and platelet-derived growth factor beta (PDGF).
Endogenous LRRK2: yes
Corresponding human genotype: R1441C is an autosomal dominant missense mutation in the LRRK2 gene.
Targeted gene: LRRK2
References: Ramones 2011, Weng 2016
- 2-3 months: The human mutated transgene is expressed 3-5 fold higher compared to the level of the endogenous LRRK2 in the cerebral cortex and cerebellum; at lower level in ventral midbrain (2 fold higher) but cannot be detected in the striatum or in the hippocampus.
- 10 months: The mutated protein is expressed in 85% of TH-positive cells in the SN.
- 12 months: No differences is observed in the number of TH-positive cells in the SN when compared to control littermates.
- 16 months: A significant loss of TH positive cells can be observed in the SN of the transgenic animals. However, contradictory results have been reported. In another study, no differences in the number of TH positive cells is observed at later time points (20-21 months).
Neurodegeneration can also be observed in the cortex, hippocampus, and striatum of the transgenic mice (NeuN staining).
- 19-20 months: Normal levels of DA and its metabolites (DOPAC, HVA) is measured in the striatum of the transgenic animals. However, a drop of the levels of dopamine, DOPAC, HVA and norepinephrine is observed in the cortex.
- Up to 16 months: No abnormalities can be seen in alpha-synuclein, phosphorylated alpha-synuclein or tau in the brain (immunostaining of brain sections).
- 6 and 12 months: No significant impairment is observed in horizontal or vertical locomotion (recorded in the open field or cylinder test).
- 15-20 months: Transgenic mice exhibit a significant decrease in velocity, distance travelled and the number of rearing events compared to control littermates.
Response to dopaminergic treatment
- 16 months: L-DOPA treatment restores motor functions in the transgenic mice (number of rearing events performed in the cylinder)
- 6 and 15 months: No impairment is observed in the sensorimotor gating abilities of the transgenic animals.
- 18 months: DA oxidation is decreased in the dorsolateral striatal slices of the transgenic animals.
- Not reported