Mouse: CB57BL/6 /DBA2 line D
Expression of the human wild type alpha-synuclein protein under the control of the platelet derived-growth factor alpha (PDGF)
Endogenous mouse alpha-synuclein: Yes
Corresponding human genotype: gene triplication in familial PD; polymorphism in the noncoding region of the alpha-synuclein locus
Transgene insertion: not reported
References: Massliah 2000; Chesselet 2012; Hatami 2015
- Expression of alpha-synuclein is observed in brain regions (neurons) with a 2-3 x increase compared to endogenous mouse alpha-synuclein levels.
- Expression of the transgene is observed in glial cells
- 12 months: Moderate loss of TH-positive terminals is detected in the striatum
- No loss of TH-positive neurons is detected in the SN at any age.
- 12 months: Significant reduction (25-50%) of striatal dopamine levels is observed
An overall high cortical pathology closely resembling DLB is observed.
- 2 months: large inclusions are observed in cell nuclei in the neocortex, CA3 region of the hippocampus, in the olfactory bulb and in the SN.
- 9-11 months: large cytoplasmic inclusions are observed in the absence of fibril formation.
- Some expression of alpha-synuclein phosphorylated at serine 129 is observed but is restricted to nuclei and perinuclear cytoplasm.
- 3-4 months: deficits in the rotarod test are detected
- 9 months: deficits in motor coordination during execution of challenging test (beam walk with grid) are detected. Overall motor activities are not affected
Response to L-DOPA treatment
- Not reported
Non motor Behaviours
Non motor impairments are observed and may be related to the high cortical and hippocampal pathology (Hatami 2015)
- 6 months : no deficits are reported
- 9-12 months : Spatial learning alterations are detected in the Morris Water Maze. These deficits can be reversed by an mGluR5 antagonist (9 months) and by reversed immunotherapy using an anti-alpha-synuclein antibody (12 months).
- Not reported
- Increased gliosis is observed in the brainstem, cerebellum, hippocampus, midbrain including the SN and in the thalamus.