PDGF-hsynwt – Mouse

General Information

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

Transgene expression

• 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

Neurodegeneration

• 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.

Dopamine Homeostasis

• 12 months: Significant reduction (25-50%) of striatal dopamine levels is observed

Inclusions

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.

Motor Behaviours

• 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).

Electrophysiology

• Not reported

Neuroinflammation

• Increased gliosis is observed in the brainstem, cerebellum, hippocampus, midbrain including the SN and in the thalamus.