Genes: SNCA, SNCA
Mutations: SNCA A53T
Modification: SNCA: Transgenic; SNCA: Knock-Out
Disease Relevance: Parkinson's Disease
Strain Name: FVB;129S6-Sncatm1Nbm Tg(SNCA*A53T)1Nbm Tg(SNCA*A53T)2Nbm/J
Genetic Background: The PAC transgene was injected into FVB/N oocytes and founder mice bred to FVB/N. The knockout mice were made in a 129S6/SvEvTac background.
Availability: Available through The Jackson Laboratory, Stock #010799; Live.
In this model, mice lacking endogenous α-synuclein (Snca knockout mice) are crossed with a line overexpressing full-length mutant human α-synuclein. Double-homozygous mice are viable into adulthood and exhibit early onset abnormalities of the enteric nervous system leading to gastrointestinal dysfunction. Neurons in the enteric nervous system of the gut develop α-synuclein pathology, but neurons in the brain are spared and there is no evidence of dopaminergic neuron loss (Kuo et al., 2010).
Homozygous mice have four copies of the human transgene (two on chromosome 3 and two on chromosome 14) and robust expression in the brain and colon. At six weeks of age, the level of transgene RNA was about 10-fold greater than the RNA level for endogenous mouse α-synuclein. However, transgenic protein levels were only slightly above endogenous levels (1.3- to twofold increase). In the colon, transgene expression at both RNA and protein levels was very high, approximately 80-fold increase.
As they aged, the double-transgenic mice (PAC-Tg(SNCAA53T)+/+; Snca-/- ) were less active than control mice. They moved around less than controls in the open-field test at six, 12, and 18 months of age. This was not attributed to differences in anxiety levels. Both males and females also performed worse on the accelerating Rotarod, compared with controls at six, 12, and 18 months of age.
By three months of age, the double mutants begin to show signs of gastrointestinal dysfunction, including abnormally small and hard fecal pellets. Further analysis showed reduced overall fecal mass with reduced water content, as well as a decrease in motility through the colon and prolonged whole-gut transit time. Despite chronic impairments to GI function, body weight in the double-transgenics did not significantly differ from non-Tg out to 18 months of age.
Neurons of the enteric nervous system expressed mutant α-synuclein and accumulated α-synuclein aggregates in the cytoplasm and nucleus with age.
The brain was remarkably intact. The double-mutant mice did not exhibit Lewy body-like pathology or signs of α-synuclein aggregation. There was no evidence of neurodegeneration in tyrosine hydroxylase (TH)-positive cells of the substantia nigra at 11 and 18 months of age. A few dystrophic neurites were observed in the hippocampus at 12 to 22 months, but otherwise brain structure was comparable to control mice. The striatal dopaminergic concentration was also comparable to non-Tg mice at 11 and 18 months of age, as were levels of dopaminergic metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC).
In this double-transgenic model, one parental line expresses mutant human α-synuclein (A53T mutation) via a 146 kb P1 artificial chromosome (PAC) containing full-length human SNCA gene and 34 kb upstream sequence. The other line is an Snca knockout line generated by replacing exons 4 and 5 with a neomycin resistance cassette.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Dopamine Deficiency
- α-synuclein Inclusions
- Neuronal Loss
- Mitochondrial Abnormalities
- Cognitive Dysfunction
No evidence of Lewy body-like inclusions in the brain at any age. Likewise α-synuclein aggregates were not observed in the brain, although they did occur in enteric neurons in the gut.
No differences in striatal dopamine concentrations, or dopaminergic metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) at 11 and 18 months of age.
By 6 months of age, homozygous mice became hypoactive, traveling less distance. This was not attributed to changes in exploratory behavior caused by anxiety. Also at 6 months, differences in performance on the accelerating Rotarod were seen.
No evidence of neuronal cell loss in the substantia nigra at 11 and 18 months of age, including dopaminergic neurons (TH-positive neurons) and total neurons.
Research Models Citations
- Kuo YM, Li Z, Jiao Y, Gaborit N, Pani AK, Orrison BM, Bruneau BG, Giasson BI, Smeyne RJ, Gershon MD, Nussbaum RL. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes. Hum Mol Genet. 2010 May 1;19(9):1633-50. PubMed.