Expression of the full-length mouse mutant FLAG-tagged (G2019S) LRRK2 protein using the bacterial artificial chromosome (BAC).
Endogenous 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.
Targeted gene: LRRK2
References: Li 2010, West 2014, Xiao 2015, Sweet 2015
- Depending on the study, the transgene expression is estimated to be 5-6 fold or up to 30 fold higher than the endogenous LRRK2 in the midbrain of transgenic animals.
- Up to 18 months: No differences in the number of tyrosine hydroxylase (TH) positive cells in the SN or in the density of TH fibres measured in the striatum. No degeneration is visible in the cortex or hippocampus.
- 6 months: No differences in the level of dopamine (DA) and its metabolite homovanillic acid (HVA) are observed in the striatum of these animals (compared to control mice).
- 10-12 months: Significant drops in the levels of DA and HVA are observed in the striatum of the LRRK2G2019S transgenic animals (compared to control mice and transgenic mice over-expressing the mouse wild-type LRRK2 gene). No difference in striatal TH protein levels, enzymatic activity, or phosphorylation state when compared to control mice. Similarly VMAT2, DAT, or D2 receptor levels are comparable to wild type animals.
- Up to 18 months: No alpha-synuclein and/or ubiquitin inclusions are visible. However, there is less phosphorylated tau positive cell in the dorsal striatum of these animals when compared to littermate control mice.
- 6 and 12 months: No differences are observed in the open field (distance travelled, total active time, rearing events) or on a challenge beam (total step, total slips or slips/step).
Response to dopaminergic treatment
- Non-applicable in absence of significant motor impairments
- Not reported
- 6 months: No changes in electrical stimulation-evoked dopamine are observed in LRRK2G2019S transgenic animals.
- 12 months: A decrease in electrical stimulation-evoked DA release and the maximum uptake rate of DA is observed in LRRK2G2019S transgenic animals compared to paired littermate control mice. Moreover, the decline in DA levels released over a 20 min stimulation period is greater that the one observed in control animals.
- 3-5 months and 8-12 months: Electrophysiological changes can be observed in the dorsal hippocampus of transgenic aged mice (8-12 months) but not in younger animals (3-5 months). LRRK2G2019S mice show an increase in basal synaptic efficiency and a decrease of long-term depression (LTD). However, no change in presynaptic function is observed.
- Not reported