PrP-hsynA53T - Mouse - JPND Neurodegenerative Disease Research

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 2007; Kurz 2010 Paumier 2013; Wang 2018; Rota 2019

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.
3-9 months: accumulation of alpha-synuclein aggregates in proximal and distal colon (Rota 2019)
3 months: accumulation of insoluble alpha-synuclein in dopaminergic and cholinergic enteric neurons (Rota 2019)
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.

2-12 months: mice develop an age-dependent anxiolytic-like phenotype (open field and stress-induced hyperthermic tests).
3, 6 and 9 months: reduced colonic motility
3 and 6 months: delayed whole gut transit time linked to GI dysmotility (not observed at 9 months)
6-12 months: development of spatial memory deficits.

Reduced basal synaptic transmission is observed in the hippocampus (Paumier 2013)
3 months: Reduced evoked motor response of colonic linked to impaired cholinergic transmission (Rota 2019)

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

Updated 20/02/2019