Overview

Also Known As:Hualpha-Syn(A53T) transgenic line G2-3

These Hualpha-Syn(A53T) transgenic mice display an age-dependent phenotype including progressive motor deficits, intraneuronal inclusion bodies and neuronal loss. This line may be useful for studying Parkinson's disease and other synucleinopathies associated with motor neuron loss and ubiquitinated inclusions in the brain stem and the spinal cord, Lewy bodies, and synaptic plasticity.

Donating Investigator

Michael K. Lee, University of Minnesota

Genetic overview

Genetic Background	Generation
	N20+N12 (2019-11-01 00:00:00)

2310039L15Rik^{Tg(Prnp-SNCA*A53T)23Mkle}

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

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Research Applications

Neurobiology Research
Research Tools

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Base Price

Starting at:

$278.00 Domestic price for female 4-week

356.51 Domestic price for breeder pair

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Details

Detailed Description

These transgenic mice express a A53T missense mutant form of human alpha-synuclein under the control of the murine prion promoter. The transgene integrated into chromosome 10 causing an 48,317 bp deletion in 2310039L15Rik. The donating investigator reports that homozygous mice are not viable. Mice hemizygous for the MoPrP-Hualpha-Syn(A53T) transgene are viable and fertile, but the donating investigator reports that female carriers do not breed well. These Hualpha-Syn(A53T) mice (also called G2-3(A53T), Hualpha-Syn(A53T), PrPsynA53T, or A53TαS Tg mice [line G2-3(A53T)]) express the familial Parkinson's disease-associated A53T missense mutant form of human alpha-synuclein (alpha-Syn or αS). Northern blot analysis shows high transgene expression in brain tissues is directed primarily to the hindbrain by the mouse prion protein promoter. Transgenic mice from line G2-3(A53T) express the A53T mutant alpha-Syn protein at approximately six times the level of endogenous mouse alpha-Syn. Hemizygous mice spontaneously develop adult-onset neurodegenerative disease between 9-16 months of age (mean age of onset is approximately 13 months, approximately 90% penetrant), with a progressive motoric dysfunction leading to death within 14-21 days of onset. Approximately 10% of the transgenic animals do not develop locomotor phenotype by 16-18 months of age. Affected mice exhibit neuronal abnormalities (in perikarya and neurites) including pathological accumulations of alpha-Syn and ubiquitin. Brain regions also show alpha-Syn-dependent neurodegeneration associated with increased/abnormal detergent-insoluble alpha-Syn and alpha-Syn aggregation. In neurons exhibiting alpha-Syn pathology, disease onset is coincident with induction of endoplasmic reticulum chaperones. Hemizygous mice also have adult onset hyperactivity associated with D1 receptor and dopamine transporter-mediated alterations in dopamine neurotransmission. These A53T mutant alpha-Syn expressing mice have significantly greater in vivo neurotoxicity when compared with A30P mutant or wildtype alpha-Syn expressing mice on the same genetic background.

This model is being used to screen for neuroprotective agents in the NINDS-funded CINAPS project.

Development

A 436 bp human alpha-synuclein cDNA bearing a familial Parkinson's disease-linked A53T missense mutation was inserted downstream of a mouse prion protein promoter. This MoPrP-Hualpha-Syn(A53T) transgene was used for pronuclear injection into one-cell (C3H/HeJ x C57BL/6J) hybrid mouse embryos. The resulting Hualpha-Syn(A53T) transgenic mice (founder line G2-3) were subsequently backcrossed to C57BL/6J mice for at least 20 generations prior to arrival at The Jackson Laboratory. The transgene integrated into chromosome 10 causing an 48,317 bp deletion in 2310039L15Rik. Upon arrival, transgenic mice were additionally bred to C57BL/6J mice to establish the colony.

Expression Data

Expressed Gene	SNCA, synuclein alpha, human
Site of Expression

Control Suggestions

Noncarrier
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Lee MK; Stirling W; Xu Y; Xu X; Qui D; Mandir AS; Dawson TM; Copeland NG; Jenkins NA; Price DL. 2002. 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 99(13):8968-73PubMed: 12084935 MGI: J:77344

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Genetics

2310039L15Rik^{Tg(Prnp-SNCA*A53T)23Mkle}

Allele Symbol: 2310039L15Rik^{Tg(Prnp-SNCA*A53T)23Mkle}

Allele Name	transgene insertion 23, Michael K Lee
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	A53T-syn; alphaSyn^Tg; G2-3; hA53Talpha-syn; Hualpha-Syn(A53T); MoPrP-Hualpha-Syn(A53T); PrP-SCNA^A53T; PrPsynA53T; Tg(Prnp-SNCA*A53T)23Dpr
Gene Symbol and Name	2310039L15Rik, RIKEN cDNA 2310039L15 gene
Gene Synonym(s)
Promoter	Prnp, prion protein, mouse, laboratory
Expressed Gene	SNCA, synuclein alpha, human
Strain of Origin	(C3H/HeJ x C57BL/6J)F1
Chromosome	10
General Note	This line was originally designated G2-3. Lines H5 and N2-5 were also generated. Mice transgenic for lines H5 and N2-5 display a phenotype similar to that displayed by mice carrying line 23. A fourth line of transgenic mice (L5) which did not develop disease, expressed a low level of the mutant human protein. Transgenic mice express high levels of mutant human Ala53Thr alpha synuclein in brain and develop an adult onset neurodegenerative disease characterized by progressive motoric dysfunction that rapidly progresses to death in most animals. Expression of the mutant protein is associated with significantly enhanced in vivo neurotoxicity. Transgenic mice develop motor signs characterized by sustained posturing, reduced amplitude, and abundance of spontaneous activity. In many instances, the affected mice seem to exhibit bradykinesia, mild ataxia, and dystonia. These mice eventually develop progressive loss of righting reflex and paralysis. Although the abundance of alpha-synuclein transcript in both human and mouse substantia nigra (SN) decreases with age, levels of alpha-synuclein protein remain at high levels, resulting in an elevated level of alpha-synuclein relative to other synucleins. The level of A53T mutant human alpha-synuclein (SNCA) protein in brains of mice of lines N2-5 and H5, adjusted for transgene copy number, becomes significantly elevated as the mice age in comparison with the brain levels of human alpha-synuclein in mice bearing similar transgenes encoding A30P mutant [Tg(Prnp-SNCAA30P)2Dpr] and wild-type [Tg(Prnp-SNCA)22Dpr] human SNCA, which do not change with age. (The present A53T mutant line, G2-3, was not analyzed in these studies because the severity of its brain pathology might interfere with the results.) (J:137012)*
Molecular Note	The transgene contains a human alpha synuclein cDNA encoding the Ala53Thr amino acid substitution, and the murine prion promoter. Line 23 inserted into the gene at 95350683-95399000 (Build GRCm38/mm10) resulting in a 48,317 bp deletion.
Mutations Made By	Michael Lee, University of Minnesota

Disease/Phenotype

Disease Terms

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Parkinson's disease 1

Research Areas By Phenotype

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

Neurobiology Research
- Neurotransmitter Receptor and Synaptic Vesicle Defects
- Ataxia (Movement) Defects
- Parkinson's Disease
  - synuclein mutants
- Neurodegeneration
Research Tools
- Neurobiology Research

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: 2310039L15Rik^{Tg(Prnp-SNCAA53T)23Mkle}/0
involves: C3H/HeJ C57BL/6J

behavior/neurological phenotype

abnormal motor capabilities/coordination/movement
- mutants develop motor signs characterized by sustained posturing, reduced amplitude, and abundance of spontaneous activity with age

ataxia

bradykinesia

dystonia

impaired righting response
- mutants eventually develop progressive loss of righting reflex

paralysis
- mutants eventually develop paralysis

mortality/aging

premature death
- within 14-21 days of onset of motor problems and disease onset, mutants rapidly progress to death most likely due to inability to feed and drink

muscle phenotype

dystonia

nervous system phenotype

abnormal nervous system morphology
- average age of onset of clinical abnormalities is 10.1 +/- 1.2 months
- neuropathological abnormalities develop before motor dysfunction is visible

abnormal neuron morphology
- abnormal neuronal accumulations are not seen in mutants younger than 4 months of age
- affected neurons contain fibrillar inclusions
- mutants exhibit accumulation of ubiquitin and phosphorylated Nefh (NF-H) in perikarya and neurites

abnormal spinal cord morphology
- spinal cord exhibits astrocytic response and ubiquitin and alpha- synuclein accumulation in ventral horn motor neurons

astrocytosis
- astroglial reaction is seen in the midbrain, deep cerebellar nuclei, brainstem and spinal cord, indicating neurodegeneration, but not in the cortex, hippocampus, thalamus, and caudate/putamen

neurodegeneration
- astroglial reaction is seen in the midbrain, deep cerebellar nuclei, brainstem and spinal cord, indicating neurodegeneration
- mutants develop adult-onset neurodegenerative disease

neuronal intranuclear inclusions
- mutants exhibit accumulation of alpha-synuclein in neuronal cell bodies and neurites of the midbrain, cerebellum, brainstem and spinal cord

References

Lee MK; Stirling W; Xu Y; Xu X; Qui D; Mandir AS; Dawson TM; Copeland NG; Jenkins NA; Price DL. 2002. 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 99(13):8968-73PubMed: 12084935 MGI: J:77344

Additional - 2310039L15Rik^{Tg(Prnp-SNCA*A53T)23Mkle} related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Pyrosequencing:** human SNCA*A53T
- Standard PCR:Tg(Prnp-SNCA*A53T)23Mkle
- Genotyping resources and troubleshooting
Dietary Information
- LabDiet® 5K52 formulation (6% fat)
Breeding Considerations

When maintaining a live colony, hemizygous males are bred to wildtype female siblings or to inbred C57BL/6J females. The donating investigator reports that female carriers do not breed well and homozygotes are not viable.
- Additional Breeding and Husbandry Support
Mating System
- See "Breeding Considerations"
Citation
When using the Hualpha-Syn(A53T) transgenic line G2-3 mouse strain in a publication, please cite the originating article(s) and include JAX stock #006823 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX12 (Maximum)

Pricing & Availability

Available

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Breeder Pair

Sex

Genotype

Price

Female
Male

Cryorecovery - Pricing

Service/Product	Description	Price
	Hemizygous or non carrier for Tg(Prnp-SNCA*A53T)23Mkle

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Also Known As:Hualpha-Syn(A53T) transgenic line G2-3

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

2310039L15RikTg(Prnp-SNCA*A53T)23Mkle

Allele Symbol: 2310039L15RikTg(Prnp-SNCA*A53T)23Mkle

Disease Terms

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: 2310039L15RikTg(Prnp-SNCA*A53T)23Mkle/0involves: C3H/HeJ * C57BL/6J

behavior/neurological phenotype

mortality/aging

muscle phenotype

nervous system phenotype

References

Additional - 2310039L15RikTg(Prnp-SNCA*A53T)23Mkle related

Genotyping Protocols

Dietary Information

Breeding Considerations

Mating System

Citation

Animal Health Reports

Live Mouse

Breeder Pair

Cryorecovery - Pricing

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

2310039L15Rik^{Tg(Prnp-SNCA*A53T)23Mkle}

Allele Symbol: 2310039L15Rik^{Tg(Prnp-SNCA*A53T)23Mkle}

Genotype: 2310039L15Rik^{Tg(Prnp-SNCAA53T)23Mkle}/0
involves: C3H/HeJ C57BL/6J

Additional - 2310039L15Rik^{Tg(Prnp-SNCA*A53T)23Mkle} related