Expression of the full-length human mutant (R1441G) LRRK2 protein using the bacterial artificial chromosome (BAC).
Endogenous LRRK2: yes
Corresponding human genotype: R1441G is an autosomal dominant missense mutation in the ROC domain of the LRRK2 gene. It is very common in familial cases of Parkinson’s disease and has a near complete penetrance.
Transgene insertion: not reported
- 3-6 months: transgene expression is observed in the cortex, cerebellum, striatum and ventral midbrain with a 5-10 fold increase compared to endogenous LRRK2
- 9-10 months: no loss of TH-positive neurons is observed in SN and VTA but a significant decrease in the average cell body size and the number of TH-positive dendrites are observed. TH striatal optical density is normal but spheroid and dystrophic neurites are present
- 9-10 months: Impaired DA release is detected in the striatum
- Not reported. However, a significant increase in phosphorylated tau protein is observed in the brain of the transgenic mice (9-10 months)
- Up to 21 months: Contradictory results have been reported. Loss of rearing is observed in the cylinder test (6-12 months) as well as hypokinesia that progresses to apparent immobility (akinesia) between 10-12 months. However, according to other studies, only mild deficits in motor behaviours are observed up to 21 months, with some coordination impairments starting at 16 months (pole test, rotarod).
Response to dopaminergic treatment
- 10-12 months: L-DOPA and Apomorphine treatments reverse the motor deficits
- Depression-like (elevated plus maze): no deficits are observed from 6 to19 months
- Anxiety-like (tail suspension and forced swimming): no deficits are observed from 6 to19 months
- Sensory responses: no olfactory deficits or changes in pain-dependent-sensory function are observed at up to 21 months.
- Learning and memory: no deficits are detected at 21 months
- Gastrointestinal function: age-dependent appearance of deficits starting at 6 months
- Not reported
- 9-10, 16 months: no gliosis is observed