Mouse: C3H/C57BL/6J x CB57BL/6J
Expression of the mutant (A53T) human alpha-synuclein protein under the control of the mouse Prion Protein (PrP) gene promoter
Endogenous mouse alpha synuclein: Yes
Corresponding human genotype: Autosomal dominant mutation in PD patients (PARK1); early onset disease
Transgene insertion: not specified
- High levels of A53T alpha-synuclein are expressed in the spinal cord, cortex, cerebellum, and midbrain of both heterozygous and homozygous mice.
- Age-dependent loss of TH-positive terminals and neurons is evidenced in the nigrostriatal pathway
- 9 and 12 months: reduction of DAT expression is measured (11C-CFT PET imaging) in the striatum of transgenic mice compared to wild type littermate.
- Increase in striatal dopamine levels are detected with aging
- Alteration of dopamine signalling (decrease of dopamine transporter) in the striatum associated with reduced dopamine reuptake is detected (Hunger 2006)
- Upregulation of dopamine receptor 1 and 2 is observed in the SN (Kurz 2010)
- 2-16 months: Inclusions (mainly in neuronal cell bodies and neurites) are observed in the spinal cord, throughout the brain stem, cerebellum, thalamus, motor cortex, and LC. Abnormal accumulation of pathological alpha-synuclein can be observed before clinical motor symptoms.
- No inclusions are detected in the olfactory bulb, hippocampus and SNc
- Co-treatments with paraquat and maneb exacerbate alpha-synuclein pathology (Erin 2007)
Mice are usually healthy without altered motor phenotype until 7 month.
- 8-18 months: development of motor phenotype (reduced ambulation, freezing of hind limb, tremulous motions) with a rapid escalation of severity leading to incapacity of feeding (Giasson 2002).
Other data show that mice, as a group, become symptomatic between 8-17 months (time for 100% of mice to develop motor symptoms) (Paumier 2013).
- 1-2 months: impairment in fine-and sensorimotor tasks including grooming, nest building and acoustic startle.
- 2-6 months: early reduction in coordination and balance (rotarod test) is observed. No differences are observed compared to non-transgenic mice at a later time point (12 months).
- 6-12 months: hyperactive mice displaying a significant increase in the total distance travelled in (open field test).
- 12 months: gait abnormality.
Response to L-DOPA treatment
- Not reported
Non motor Behaviours
- 2-12 months: mice develop an age-dependent anxiolytic-like phenotype (open field and stress-induced hyperthermic tests).
Reduced colonic motility is observed (3, 6 and 9 months).
- 6-12 months: development of spatial memory deficits.
- Reduced basal synaptic transmission is observed in the hippocampus (Paumier 2013)
- Astrogliosis (increased expression of GFAP) is observed in brain regions affected by alpha-synuclein accumulation