Overview

Also Known As:dbl-PAC-Tg(SNCAA53T);Snca-/-

These double transgenic homozygous mice (dbl-PAC-Tg(SNCA^A53T);Snca^-/- mice) harbor a Snca knock-out allele and two independently inserted transgenes encoding the human A53T-mutant α-synuclein associated with autosomal dominant Parkinson's disease. The very early gastrointestinal dysfunction in the absence of major central nervous system pathology in dbl-PAC-Tg(SNCA^A53T);Snca^-/- mice mimics what is seen early in human Parkinson's disease, when enteric nervous system dysfunction may precede the more classical motor symptoms by years to decades.

Donating Investigator

Robert L Nussbaum, University of California San Francisco

Genetic overview

Genetic Background	Generation
	F?+F26 (2020-04-13 00:00:00)

Tg(SNCA*A53T)1Nbm

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

Tg(SNCA*A53T)2Nbm

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

Snca^tm1Nbm

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Snca	synuclein, alpha

View Genetics

Research Applications

Internal/Organ Research
Neurobiology Research
Research Tools

View All Research Applications

Base Price

Starting at:

$255.00 Domestic price for female 4-week

View Price List

Details

Detailed Description

These double transgenic homozygous mice (dbl-PAC-Tg(SNCA^A53T);Snca^-/- mice) are viable and fertile, harboring a Snca knockout allele and two independently inserted transgenes encoding the human A53T-mutant α-synuclein associated with autosomal dominant Parkinson's disease. As homozygotes, expression of endogenous mouse α-synuclein is abolished and replaced by α-synuclein*A53T from the four total insertions of the PAC-Tg(SNCA^A53T). While brain RNA expression of SNCA^A53T is ~10-fold greater compared to normal endogenous mouse α-synuclein, protein levels are only 1 to 1.5-fold greater. In colon however, both RNA and protein expression of SNCA^A53T are ~80-fold greater than normal endogenous mouse α-synuclein. By three months of age, dbl-PAC-Tg(SNCA^A53T);Snca^-/- mice show robust abnormalities in enteric nervous system function (impaired colonic motility [males only] and prolonged gut transit time). Significant α-synuclein*A53T aggregation is observed in colonic myenteric plexus, while no widespread aggregation in brain is reported. Subtle motor behavior abnormalities develop between 6-12 months. No detectable autonomic abnormalities, olfactory dysfunction, dopaminergic deficits, Lewy body inclusions or neurodegeneration are associated with α-synuclein*A53T expression in these double transgenic mice. The very early gastrointestinal dysfunction in the absence of major central nervous system pathology in dbl-PAC-Tg(SNCA^A53T);Snca^-/- mice mimics what is seen early in human Parkinson's disease, when enteric nervous system dysfunction may precede the more classical motor symptoms by years to decades.

Development

To generate the PAC-Tg(SNCA^A53T) transgene, the 146 kb RPCI-1 human male P1 artificial chromosome (PAC) clone 27M07, containing the entire human SNCA (synuclein, alpha (non A4 component of amyloid precursor)) gene and 34 kb of its upstream region, was modified to have the A53T human mutation associated with autosomal dominant Parkinson's disease (G>A substitution at base 420 of the cDNA sequence). This transgene was microinjected into the pronuclei of fertilized FVB/N ova. Each transgenic founder mouse was bred to FVB/N wildtype mice to generate the individual founder lines (1 and 2). Each PAC-Tg(SNCA^A53T) transgenic line was independently maintained as coisogenic on the FVB/N genetic background by breeding together as homozygotes.

To generate the Snca knockout allele, a targeting vector was designed to replace exons 4 and 5 with a reverse-oriented neomycin resistance cassette (PGK-neo from the vector pPNT). The construct was electroporated into 129S6/SvEvTac-derived TC-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and the resulting mutant mice were generated and maintained as coisogenic on the 129S6/SvEvTac genetic background.

To generate the dbl-PAC-Tg(SNCA^A53T);Snca^-/- strain, homozygous PAC-Tg(SNCA^A53T) line 1 mice (FVB/N genetic background) were bred with mice homozygous for the Snca knockout allele (129S6/SvEvTac genetic background). Similarly, PAC-Tg(SNCA^A53T) line 2 homozygotes were bred with Snca knockout mice. These two mutant strains were then intercrossed and bred to homozygosity to create the double transgenic strain. As homozygotes, dbl-PAC-Tg(SNCA^A53T);Snca^-/- mice were found to carry four insertions of the PAC-Tg(SNCA^A53T) transgene; two for the line 1 insert (on chomsome 3) and two for the line 2 insert (on chromosome 14). This double transgenic strain was maintained on a mixed FVB/N;129S6/SvEvTac background using multiple breeding units without repeated brother-sister matings: thus the only portions of the FVB/N or 129S6/SvEvTac genomes fixed in these mice are the FVB/N regions flanking the PAC-Tg(SNCA^A53T) transgene insertion sites and the 129S6/SvEvTac regions around the Snca knockout allele. The dbl-PAC-Tg(SNCA^A53T);Snca^-/- mice were sent to The Jackson Laboratory Repository. Upon arrival, mice were bred together to establish the colony.

Expression Data

Expressed Gene	SNCA, synuclein alpha, human
Site of Expression
Expressed Gene	SNCA, synuclein alpha, human
Site of Expression
Site of Expression

Control Suggestions

None Available

Additional Information

Considerations for Choosing Controls

Selected References

Cabin DE; Shimazu K; Murphy D; Cole NB; Gottschalk W; McIlwain KL; Orrison B; Chen A; Ellis CE; Paylor R; Lu B; Nussbaum RL. 2002. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22(20):8797-807PubMed: 12388586 MGI: J:79784
Kuo YM; Li Z; Jiao Y; Gaborit N; Pani AK; Orrison BM; Bruneau BG; Giasson BI; Smeyne RJ; Gershon MD; Nussbaum RL. 2010. 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 19(9):1633-50PubMed: 20106867 MGI: J:156741

View All References

Genetics

Tg(SNCA*A53T)1Nbm

Allele Symbol: Tg(SNCA*A53T)1Nbm

Allele Name	transgene insertion 1, Robert L Nussbaum
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	hSNCA^A53T; PAC-Tg(SCNA^A53T)
Gene Symbol and Name	Tg(SNCA*A53T)1Nbm, transgene insertion 1, Robert L Nussbaum
Gene Synonym(s)
Promoter	SNCA, synuclein alpha, human
Expressed Gene	SNCA, synuclein alpha, human
Strain of Origin	FVB/N
Chromosome	UN
Molecular Note	To generate the PAC-Tg(SNCAA53T) transgene, the 146 kb RPCI-1 human male P1 artificial chromosome (PAC) clone 27M07, containing the entire human SNCA (synuclein, alpha (non A4 component of amyloid precursor)) gene and 34 kb of its upstream region, was modified to have the A53T human mutation associated with autosomal dominant Parkinson's disease. This transgene was microinjected into the pronuclei of fertilized FVB/N ova. One transgenic insertion is present in the genome.

Tg(SNCA*A53T)2Nbm

Allele Symbol: Tg(SNCA*A53T)2Nbm

Allele Name	transgene insertion 2, Robert L Nussbaum
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	hSCNA^A53T; PAC-Tg(SCNA^A53T)
Gene Symbol and Name	Tg(SNCA*A53T)2Nbm, transgene insertion 2, Robert L Nussbaum
Gene Synonym(s)
Promoter	SNCA, synuclein alpha, human
Expressed Gene	SNCA, synuclein alpha, human
Strain of Origin	FVB/N
Chromosome	UN
Molecular Note	To generate the PAC-Tg(SNCAA53T) transgene, the 146 kb RPCI-1 human male P1 artificial chromosome (PAC) clone 27M07, containing the entire human SNCA (synuclein, alpha (non A4 component of amyloid precursor)) gene and 34 kb of its upstream region, was modified to have the A53T human mutation associated with autosomal dominant Parkinson's disease. This transgene was microinjected into the pronuclei of fertilized FVB/N ova. One transgenic insertion is present in the genome.

Snca^tm1Nbm

Allele Symbol: Snca^tm1Nbm

Allele Name	targeted mutation 1, Robert L Nussbaum
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Scna-; Snca^-
Gene Symbol and Name	Snca, synuclein, alpha
Gene Synonym(s)
Strain of Origin	129S6/SvEvTac
Chromosome	6
Molecular Note	Exons 4 and 5 were replaced with a neomycin selection cassette inserted by homologous recombination. While the separation of Western blot results by 2D-PAGE showed various isoforms in total brain extract obtained from wild-type mice, protein was undetected in samples obtained from homozygous mutant mice.

Disease/Phenotype

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Parkinson's disease 1

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Internal/Organ Research
- Gastrointestinal Defects
Neurobiology Research
- Ataxia (Movement) Defects
- Parkinson's Disease
  - synuclein mutants
Research Tools
- Neurobiology Research

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Snca^tm1Nbm/Snca^tm1Nbm Tg(SNCAA53T)1Nbm/Tg(SNCAA53T)1Nbm Tg(SNCAA53T)2Nbm/Tg(SNCAA53T)2Nbm
involves: 129S6/SvEvTac * FVB/N

behavior/neurological phenotype

hypoactivity
- distance traveled decreases with age, showing reduced ambulatory distance traveled compared to controls at 12 and 18 months; reduction is generalized, not specific to a particular type of movement or region
- total distance traveled in the open field apparatus is reduced compared to controls at 6 months and remains abnormal at 18 months

impaired coordination
- males and females exhibit consistently reduced latency to fall beginning at 6 months; this persisted at 1 year of age and more pronounced at 18 months; endurance and coordination in the rotating rod test are abnormal

mammalian phenotype

cardiovascular system phenotype
- Normal - no defects in autonomic cardiac innervation are detected

growth/size/body region phenotype
- Normal - body weigh does not differ from controls measured out to 18 months of age

nervous system phenotype
- Normal - dorsal motor nucleus of the vagus shows no abnormal alpha-synuclein aggregation and any widespread aggregates are not detected in brain homogenates of 5 and 18 month-old animals
- Normal - no progressive loss of dopaminergic neurons in the substantia nigra, pars compacta (SNpc) is observed
- Normal - olfaction and cardiac innervation by the autonomic nervous system are not affected by the transgenes
- Normal - striatal tissue dopamine and dopamine metabolite content are not different from controls at 11 and 18 months

taste/olfaction phenotype
- Normal - mice show no impairments in olfaction at 12 and 18 months of age
- Normal - olfactory bulbs show no degeneration or protein aggregation at 12 and 18 months of age

nervous system phenotype

abnormal hippocampus morphology
- some dystrophic synapses are observed in rare instances at 12 or 22 months

alpha-synuclein inclusion body
- most alpha-synuclein positive neurons, especially in the myenteric plexus are not coincident with TH immunostaining
- protein is present in tyrosine hydroxylase (TH)-immunoreactive neuronal cell bodies within myenteric and submucosal plexuses; varicose TH-positive terminals of noradrenergic sympathetic neurons
- proteinase K-resistant alpha-synuclein aggregates are observed in the nuclear and perinuclear cytoplasm of enteric nervous system neurons in mice showing gastrointestinal motility dysfunction

digestive/alimentary phenotype

abnormal digestive system physiology
- proteinase K-resistant alpha-synuclein aggregates are observed in the nuclear and perinuclear cytoplasm of enteric nervous system neurons in mice showing gastrointestinal motility dysfunction

abnormal intestinal transit time
- stal colonic motility)
- whole-gut transit time (WGTT) is prolonged compared to controls starting at 3 months and is markedly prolonged at 6 months persisting through 18 months of age; this phenotype does not differ between males and females in contrast to bead expulsion time (distal colonic motility)

abnormal large intestinal transit time
- amount of stool passed/unit time and stool water content are unchanged at 3 months of age but by 6 months these parameters are reduced to comparable degrees
- motility of distal colon is reduced compared to controls with males showing around a 4-5 fold prolongation in expulsion compared to controls; reduction is exaggerated compared to females
- this phenotype is present at 3 months and persists through 18 months of age

References

Cabin DE; Shimazu K; Murphy D; Cole NB; Gottschalk W; McIlwain KL; Orrison B; Chen A; Ellis CE; Paylor R; Lu B; Nussbaum RL. 2002. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22(20):8797-807PubMed: 12388586 MGI: J:79784
Kuo YM; Li Z; Jiao Y; Gaborit N; Pani AK; Orrison BM; Bruneau BG; Giasson BI; Smeyne RJ; Gershon MD; Nussbaum RL. 2010. 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 19(9):1633-50PubMed: 20106867 MGI: J:156741

Additional - Snca^tm1Nbm related

Additional - Tg(SNCA*A53T)1Nbm related

Additional - Tg(SNCA*A53T)2Nbm related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- QPCR:Tg(SNCAcDNA)-qPCR
- Standard PCR:Tg(SNCA)129Mjff
- Standard PCR:Tg(SNCA)
- Genotyping resources and troubleshooting
Dietary Information
- LabDiet® 5K52 formulation (6% fat)
Breeding Considerations

When maintaining a live colony, mice homozygous for the Snca targeted mutation and homozygous for both Tg(SNCA^A53T) transgenes are bred together. The experimental control strain is Stock No. 010710.
- Additional Breeding and Husbandry Support
Mating System
- See "Breeding Considerations"
Citation
When using the FVB;129S6-Snca^tm1Nbm Tg(SNCA*A53T)1Nbm Tg(SNCA*A53T)2Nbm/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #010799 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX10 (Standard)

Pricing & Availability

Available

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Homozygous for Snca<tm1Nbm>, Homozygous forTg(SNCAA53T)1Nbm , Homozygous forTg(SNCAA53T)2Nbm/J

Related Products and Services

Frozen Mouse Embryo	FVB;129S6-Snca<tm1Nbm> Tg(SNCA*A53T)1Nbm Tg(S Frozen Embryos	$2595.00
Frozen Mouse Embryo	FVB;129S6-Snca<tm1Nbm> Tg(SNCA*A53T)1Nbm Tg(S Frozen Embryos	$2595.00
Frozen Mouse Embryo	FVB;129S6-Snca<tm1Nbm> Tg(SNCA*A53T)1Nbm Tg(S Frozen Embryos	$3373.50
Frozen Mouse Embryo	FVB;129S6-Snca<tm1Nbm> Tg(SNCA*A53T)1Nbm Tg(S Frozen Embryos	$3373.50

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Also Known As:dbl-PAC-Tg(SNCAA53T);Snca-/-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Tg(SNCA*A53T)1Nbm

Allele Symbol: Tg(SNCA*A53T)1Nbm

Tg(SNCA*A53T)2Nbm

Allele Symbol: Tg(SNCA*A53T)2Nbm

Sncatm1Nbm

Allele Symbol: Sncatm1Nbm

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Sncatm1Nbm/Sncatm1Nbm Tg(SNCA*A53T)1Nbm/Tg(SNCA*A53T)1Nbm Tg(SNCA*A53T)2Nbm/Tg(SNCA*A53T)2Nbminvolves: 129S6/SvEvTac * FVB/N

behavior/neurological phenotype

mammalian phenotype

nervous system phenotype

digestive/alimentary phenotype

References

Additional - Sncatm1Nbm related

Additional - Tg(SNCA*A53T)1Nbm related

Additional - Tg(SNCA*A53T)2Nbm related

Genotyping Protocols

Dietary Information

Breeding Considerations

Mating System

Citation

Animal Health Reports

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Snca^tm1Nbm

Allele Symbol: Snca^tm1Nbm

Genotype: Snca^tm1Nbm/Snca^tm1Nbm Tg(SNCAA53T)1Nbm/Tg(SNCAA53T)1Nbm Tg(SNCAA53T)2Nbm/Tg(SNCAA53T)2Nbm
involves: 129S6/SvEvTac * FVB/N

Additional - Snca^tm1Nbm related