PITX3-tTA-hsynA53T – Mouse

General Information

Mouse: CB57BL/6J

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

Transgene expression

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.

Neurodegeneration

• 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

Dopamine Homeostasis

• 1, 3 and 4 months: reduced dopamine levels and reduced evoked dopamine release are detected in the striatum.

Inclusions

• 12 and 18 months: abnormal accumulation of alpha synuclein (including aggregates) is observed in cytosol and axons of midbrain dopaminergic neurons

Motor Behaviours

• 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

Electrophysiology

• Not reported

Neuroinflammation

• 20 months: increased astrocytosis and microgliosis is observed in the brain