Mutations: SNCA A53T
Modification: SNCA: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: B6.Cg-2310039L15RikTg(Prnp-SNCA*A53T)23Mkle/J. Formerly: B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J
Genetic Background: Established as C3H/HeJ x C57BL6/J hybrids, then maintained by backcrossing to C57Bl6/J.
Availability: Available through The Jackson Laboratory, Stock# 006823, Live.
These transgenic mice overexpress human α-synuclein with a PD-associated mutation (A53T). Hemizygous mice overexpress mutant α-synuclein in the brain at levels about sixfold higher than endogenous mouse α-synuclein. They develop severe progressive motor impairments around one year of age, but no overt neuronal loss (Lee et al., 2002). The data on this page refer to phenotypes observed in hemizygous animals; homozygous mice from this strain are not viable.
The mouse prion protein (PrP) promotor drives transgene expression in these mice, resulting in widespread neuronal expression. In situ hybridization confirmed expression in neurons of the substantia nigra pars compacta. Expression was also observed in glia cells. Human α-synuclein protein appeared in a punctate pattern in the neuropil, suggesting enrichment at presynaptic terminals.
Interestingly, prior to symptom onset the G2-3 mice are generally more active than non-Tg mice. However, around 10 months of age they begin to develop severe motor impairments (Lee et al., 2002). [Note, onset is described as nine to 16 months on the Jackson Lab web page, October 2016]. Early signs of impairment include wobbling and posturing. Within a few days, total locomotor activity decreases and spontaneous movements slow. The mice become unable to navigate the Rotarod. Stiffness of the tail was noted. Ultimately, the mice are unable to right themselves and reach end-stage disease, typically within 14–21 days of onset. The motor phenotype is reportedly about 90 percent penetrant, with 10 percent of mice escaping impairment at 16 to 18 months of age (Jackson Lab web page; October 2016).
Neuropathologically, affected G2-3 mice exhibit accumulation of α-synuclein protein in certain neuronal populations, including the midbrain, cerebellum, brainstem, and spinal cord (including ventral horn motor neurons). In addition, these neurons accumulate ubiquitin and phosphorylated neurofilament-H. The protein aggregates do not resemble Lewy bodies, but are thioflavin-S-positive, indicating a fibrillar structure. These protein accumulations were absent in young mice (two to four months of age) but were detectable in presymptomatic older mice. Although the transgene is expressed in the substantia nigra, significant pathology was not observed in this region and there was no significant loss of striatal dopamine, or the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).
Reactive gliosis is another neuropathological feature of these mice. Compared to age-matched non-Tg controls, symptomatic G2-3 mice exhibited higher levels of GFAP immunoreactivity in the midbrain, deep cerebellar nuclei, brainstem, and spinal cord. In contrast, GFAP immunoreactivity was comparable to controls in the cortex, hippocampus, thalamus, and caudate/putamen.
Hemizygous G2-3 mice are viable and fertile prior to symptom onset, but female carriers do not breed well (Jackson Lab web page; October 2016).
The transgene consists of the human α-synuclein sequence with the A53T mutation driven by the mouse prion protein (PrP) promoter. The transgene inserted at Chr10:95350683-95399000 (Build GRCm38/mm10), causing a 249 Kb deletion that disrupted the 2310039L15Rik gene, which codes for a lincRNA (Goodwin et al., 2017).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Dopamine Deficiency
- Mitochondrial Abnormalities
- Cognitive Dysfunction
In symptomatic G2-3 mice, striatal dopamine and metabolites DOPAC and HVA were comparable to levels measured in non-Tg mice.
Prior to motor deficits, these mice develop accumulations of α-synuclein in select neuronal populations, including the midbrain, cerebellum, brainstem, and spinal cord. The protein aggregates do not resemble Lewy bodies, but are thioflavin-S-positive, indicating fibrillar structure.
Overt neuronal loss was not reported in these mice.
In symptomatic mice, increased GFAP immunoreactivity was observed in select brain regions, including the dorsal midbrain, deep cerebellar nuclei, brainstem, and spinal cord. Cortex, hippocampus, and substantia nigra did not have increased reactivity compared with non-Tg controls.
These mice develop severe motor impairment starting around 9-16 months of age. The deficits start out with mild hyperactivity and progress to a wobbling movement, decreased activity, and ultimately paralysis and death.
- Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL. Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8968-73. PubMed.
- Goodwin LO, Splinter E, Davis TL, Urban R, He H, Braun RE, Chesler EJ, Kumar V, van Min M, Ndukum J, Philip VM, Reinholdt LG, Svenson K, White JK, Sasner M, Lutz C, Murray SA. Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. bioRxiv preprint first posted online Dec. 18, 2017