The full-length human mutant (G2019S) LRRK2 gene was introduced in Sprague-Dawley wild type rats using the bacterial artificial chromosome (BAC).
Endogenous rat LRRK2: yes
Corresponding human genotype: The G2019S substitution in the LRRK2 gene is believed to be the most common mutation associated with Parkinson’s disease. It is located in the kinase domain of the protein.
Mutated gene: LRRK2
References: West 2014, Walker 2014, Lee 2015, Sloan 2016, Volpicelli-Daley 2016
- The transgene is expressed throughout the brain, including the midbrain, hippocampus and cortex. The level of the human mutant LRRK2 protein is 12-30 times higher compared to the level of endogenous rat LRRK2 (depending on the study).
- Up to 12months: No loss of TH positive neurons in the SN or TH density in the dorsal striatum is detected. However, DA neurons in the SN of 12 months old transgenic animals appear altered with abnormally elongated cell bodies.
- Up to 12 months: No changes in striatal levels of DA, DOPAC or in DA turnover rates is observed. Levels of HVA are higher in transgenic animals at 12 months (but not at 8 months).
No dopaminergic abnormalities are observed using PET imaging (VMAT2, DAT and D2 receptors densities and DA release)
- 3-6 months: No inclusions positive for phosphorylated alpha-synuclein are observed in the SN. However, transgenic rats are more prone to inclusions when exposed to α-synuclein triggers (e.g. viral transduction or fibril intra-cerebral injection).
- 18-21 months: No inclusions positive for alpha-synuclein, phosphorylated tau or ubiquitin are observed in the SN.
- Up to 12 months: No prominent behavioural impairment is observed up to 12 months. A slight increase in postural instability is observed at 8 months only (not at 4 or 12 months). An increase in the number of rearing events is detected at 12 months (but only in some studies). Performances on the ledge-beam (number of steps and errors per step), drag test and grip test are not altered (3, 6 and 12 months).
Conflicting results have been reported on the rotarod: transgenic animals performing better than wild type animals in some studies but significantly worse in others (3-6 months).
- 18-21 months: Transgenic animals perform significantly worse that wild type animals on the rotarod but they don’t display any gait abnormality or weakness in grip strength.
Response to dopaminergic treatment
- 18-21 months: L-DOPA restores performances of the transgenic animals on the rotarod.
3-6 months: Spatial short-term memory is not affected (spontaneous alternation test).
- 18-21 months: Transgenic animals perform significantly worse than the wild type rats in the spatial short memory test (spontaneous alternation test).
- 6 and 12 months: No changes in electrical stimulation-evoked DA are observed in the dorsal or ventral striatum. DA content and reuptake rate are not altered.
- 18-21 months: A decrease in electrical stimulation-evoked DA release is observed in the dorsal striatum. DA content and reuptake rate are not altered suggesting a reduced ability to release DA. No difference in the firing rates of SN dopamine neurons is observed.
- 12 months: There is no difference between transgenic and non-transgenic animals in terms of number, density or morphology of microglia cells present the SN. Similarly, no evidence of astrocytes activation is observed.
- 18-21 months: No changes in the number of glial cells (microglia) are observed compared to non-transgenic littermates.