Expression of the mutant (A53T) human alpha-synuclein under the control of the pituitary homeobox 3 (PITX3) promoter and the tetracycline-regulated tet-off system (tTA).
Endogenous alpha synuclein: Yes
Corresponding human genotype: Autosomal dominant mutation in PD patients (PARK1/PARK4)
Transgene insertion: not reported
References: Lin 2012
Doxycycline can be given to breeder mice and pups to supress expression of transgene from early embryonic stages to weaning ages.
- 1 months: Increased expression (2-4 x) of the mutant alpha-synuclein protein is observed in midbrain neurons. Some expression is detected in the cerebral cortex, cerebellum, olfactory bulb hippocampus and spinal cord, as well as in the eye.
- 1-12 months: progressive loss of TH-positive neurons is detected in the SN (15-40%)
- 12-20 months: no further loss of TH-positive neurons is observed in the SN
- 12 months: reduced neurite complexity is detected in in the striatum
- 1, 3 and 4 months: reduced dopamine levels and reduced evoked dopamine release are detected in the striatum.
- 12 and 18 months: abnormal accumulation of alpha synuclein (including aggregates) is observed in cytosol and axons of midbrain dopaminergic neurons
- 1-12 months: strong reduction in vertical movements (open field test) as well as unsteady and shorter gaits in the automatic gait test are observed. Rearing deficits at 1 month can be prevented with doxycycline treatment.
- 2-12 months: a moderate decrease in horizontal movement is observed in the open field test. A reduced latency to fall is measured in the rotarod test.
Response to L-DOPA treatment
- Not reported
Non motor Behaviours
- 2-24 months: reduced body gain is measured compared to wild type mice
- Not reported
- 20 months: increased astrocytosis and microgliosis is observed in the brain