General Information

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

References: Giasson 2002; Lee 2002;  Hunger 2006; Erin 2007Kurz 2010 Paumier 2013Wang 2018

Transgene expression

  • High levels of A53T alpha-synuclein are expressed in the spinal cord, cortex, cerebellum, and midbrain of both heterozygous and homozygous mice.

Neurodegeneration

  • 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. 

Dopamine Homeostasis

  • 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)

Inclusions

  • 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)

Motor Behaviours

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.

Electrophysiology

  • Reduced basal synaptic transmission is observed in the hippocampus (Paumier 2013)

Neuroinflammation

  • Astrogliosis (increased expression of GFAP) is observed in brain regions affected by alpha-synuclein accumulation

 

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