JAX Mouse Strain Datasheet - 012442

STOCK Tg(tetO-SNCA*A53T)E2Cai/J

Stock No:: 012442

Transgenic

Cryo Recovery

Overview

These transgenic mice carry a humanized synuclein (alpha-syn) mutant (SNCA*A53T) gene regulated by a tetracycline operator (tetO). When mated to a mutant strain expressing tTA, expression of SNCA*A53T protein may be regulated with the tetracycline analog doxycycline in the double mutant offspring.

Donating Investigator

Huaibin Cai, National Institutes of Health / National Institute on Aging (NIH/NIA)

Genetic overview

Genetic Background	Generation

Tg(tetO-SNCA*A53T)E2Cai

Allele Type
Transgenic (Humanized sequence, Inducible, Inserted expressed sequence)

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Research Applications

Neurobiology Research
Research Tools

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Base Price

Starting at:

$2,595.00 Domestic price Cryo Recovery

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Details

Detailed Description

Mice hemizygous for the human synuclein (alpha-syn) mutant transgene, (SNCA*A53T) are viable and fertile. Expression of SNCA*A53T is regulated by the tetracycline operator (tetO); also called tetracycline-responsive element (TRE, TetRE) or tet-operator). When mated to a mutant strain expressing tetracycline-controlled transactivator protein (tTA), expression of SNCA*A53T protein may be regulated with tetracycline or its analog doxycycline (dox) in the double mutant offspring. Mutations in alpha-syn greatly accelerate the formation of fibrillar aggregates causing various forms of cytotoxicity, including impairment of proteasomal and lysosomal activities, disruption of ER-Golgi traffic and microtubule-based transport, and dysfunction of mitochondria. SNCA*A53T mice develop age-dependent, progressive neurodegeneration. These mice may be useful for studying the Parkinson's disease pathogenesis and neurodegeneration elicited by the toxic effects of aggregation and somatic accumulation of SNCA.

Development

A transgene was generated encoding a human SNCA*A53T mutant gene under control of a tetO promoter. The construct was microinjected into C57BL/6J fertilized oocytes, and founder mice were bred to C57BL/6J mice to establish a colony. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

A 32 SNP (single nucleotide polymorphism) panel analysis performed by The Jackson Laboratory revealed 10 of 32 markers (on six different chromosomes) that were not C57BL/6J allele-type. These data suggest C57BL/6N, FVB, and/or other genetic contamination prior to arrival at The Jackson Laboratory.

Expression Data

Expressed Gene	SNCA, synuclein alpha, human
Site of Expression

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Lin X; Parisiadou L; Gu XL; Wang L; Shim H; Sun L; Xie C; Long CX; Yang WJ; Ding J; Chen ZZ; Gallant PE; Tao-Cheng JH; Rudow G; Troncoso JC; Liu Z; Li Z; Cai H. 2009. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64(6):807-27. PubMed: 20064389 MGI: J:156512

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Genetics

Tg(tetO-SNCA*A53T)E2Cai

Allele Symbol: Tg(tetO-SNCA*A53T)E2Cai

Allele Name	transgene insertion E2, Huaibin Cai
Allele Type	Transgenic (Humanized sequence, Inducible, Inserted expressed sequence)
Allele Synonym(s)	alpha-syn A53T; tetO-A53T
Gene Symbol and Name	Tg(tetO-SNCA*A53T)E2Cai, transgene insertion E2, Huaibin Cai
Gene Synonym(s)	alpha-syn A53T; tetO-A53T
Promoter	tetO, tet operator,
Expressed Gene	SNCA, synuclein alpha, human
Strain of Origin	C57BL/6J
Chromosome	UN
Molecular Note	A transgenic vector was generated encoding a human SNCA*A53T mutant gene under control of a tetO promoter. The construct was microinjected into C57BL/6J fertilized oocytes, and founder mice were bred to C57BL/6J mice to establish the E2 line.
Mutations Made By	Huaibin Cai, National Institutes of Health / National Institute on Aging (NIH/NIA)

Disease/Phenotype

Disease Terms

Research Areas By Genotype

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

Neurobiology Research
- Neurodegeneration
- Parkinson's Disease
  - synuclein mutants
- Tet Expression System
  - tTA/rtTA Responsive Strains
Research Tools
- Tet Expression Systems
  - tTA/rtTA Responsive Strains

Mammalian Phenotype Terms by Genotype

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

Genotype: Slc6a3^tm4.1(tTA)Xz/Slc6a3⁺ Tg(tetO-SNCAA53T)E2Cai/0
involves: 129S4/SvJaeSor 129S6/SvEvTac * C57BL/6

nervous system phenotype

abnormal axon morphology
- 25 fold increase in enlarged axon varicosities in midbrain region at 6 weeks of age
- varicosities are approximately 10 um in diameter, are oval-shaped and have a hollowed core

abnormal dendrite morphology
- fragmented dendrites are observed in the substantia nigra pars reticulata at 6 weeks of age

decreased dopamine level
- levels of dopamine and its metabolites (DOPA and HVA) are decreased by 54% in 7-11 month old mice in striatal tissue

loss of dopaminergic neurons
- 21% dopaminergic neuron loss in the substantia nigra pars compacta (SNc) by 3 months of age
- 35% loss by 6 months of age
- decrease in TH (tyrosine hydroxylase) terminal staining in the dorsal, but not ventral, striatum of 12 month old mice
- dopamine turnover rate is increased by 29%
- loss appears to stop or slow between 6 and 12 months

neuron degeneration

neuronal cytoplasmic inclusions
- "mitochondrial inclusions" are observed in dopaminergic neurons beginning at 3 weeks of age
- inclusions are 0.5-2 um in diameter and are labeled by mitochondrial markers (COX1, SOD2)
- inclusions are distributed in soma and proximal processes of dopaminergic neurons
- inclusions are mostly restricted to substantia nigra pars compacta
- number of inclusions is approximately 1.6 inclusions per dopaminergic neuron at 3 weeks of age
- the number of inclusions is decreased by 6 months of age

growth/size/body region phenotype

slow postnatal weight gain

homeostasis/metabolism phenotype

decreased dopamine level
- levels of dopamine and its metabolites (DOPA and HVA) are decreased by 54% in 7-11 month old mice in striatal tissue

cellular phenotype

abnormal mitochondrial physiology
- multiple senescent mitochondria are observed in dopaminergic neurons as compared to controls
- senescent mitochondria exhibit disordered cristae, swollen matrix and the absent outer membranes

abnormal mitochondrial shape
- mitochondria in dopaminergic neurons appears fragmented by 6 weeks of age

decreased mitochondria size
- mitochondrial length is decreased by 61% in mitochondria from dopaminergic neurons, however, mitochondrial mass is similar to controls

Genotype: Tg(Camk2a-tTA)1Mmay/0 Tg(tetO-SNCA*A53T)E2Cai/0
involves: C57BL/6

growth/size/body region phenotype

decreased body weight
- A53T mice weigh significantly less than non transgenic mice and Tg(tetO-SNCA*A53T)E2Cai or Tg(Camk2a-tTA)1Mmay single mutants starting at 4 months of age

behavior/neurological phenotype

abnormal locomotor activation

hyperactivity
- at 2 months of age, mice show drastically increased ambulatory activity

increased vertical activity
- mice display elevated rearing activities at 6 months of age

nervous system phenotype

abnormal cerebral cortex morphology
- in 6 month old mice but not in nontransgenic controls, elevated levels of ubiquitin are detected in somas and nuclei of cortical neurons, but
- neuron loss is detected at 6 months and later

abnormal nervous system morphology
- only a few neurons in the brain display alpha-synuclein staining in the cell body at 3 months; somatic accumulation becomes more prominent at 20 months; whereas no accumulation is detected in cell bodies at 1 month
- significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression

abnormal nervous system physiology
- brain homogenates contain significantly elevated levels of ubiquitinated proteins at 3 months
- in 6 month old mice, elevated levels of ubiquitin are detected in somas and nuclei of cortical neurons; at 20 monts, a punctate staining pattern at neuronal processes is observed
- while 3-month old A53T mice show no abnormal neuropathology, but neuropathology is evident at 12 and 20 months

abnormal neuron morphology
- at 1 month, the medial/trans-Golgi in neurons is significantly altered with ratio of fragmented trans-Golgi significantly increased compared to non-transgenic animals
- significant increase in Golgi fragmentation is observed at 6 months
- significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression
- the Golgi complex is drastically altered in neurons at 1 month, appearing thinner and fragmented

abnormal striatum morphology
- neuron loss is detected at 6 months and later
- significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression

alpha-synuclein inclusion body
- a significant increase in detergent-insoluble high molecular weight (HMW) alpha synuclein is detected in 12 month old mice compared to 1 month old mice
- significant decrease in HMW alpha-synuclein in total brain homogenates is observed when animals are treated with doxycycline to inhibit transgene expression

astrocytosis
- significant at 12 months
- significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression

microgliosis
- significant at 12 months
- significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression

neurodegeneration
- a significant reduction (>30%) of striatal neurons is seen at 6 months
- age-dependent, progressive neurodegeneration occurs
- neuronal loss is detected in the frontal cortex (>80%) and dorsal striatum (>74%) at 20 months
- widespread degeneration is observed at 20 months

hematopoietic system phenotype

microgliosis
- significant at 12 months
- significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression

immune system phenotype

microgliosis
- significant at 12 months
- significant rescue of phenotype is observed when animals are treated with doxycycline to inhibit transgene expression

cellular phenotype

abnormal mitochondrion morphology
- in striatal neurons at 1 month, numerous mitochondria have denser matrices and widened cristae compared to non-transgenic controls; these mitochondria are not functional

References

Lin X; Parisiadou L; Gu XL; Wang L; Shim H; Sun L; Xie C; Long CX; Yang WJ; Ding J; Chen ZZ; Gallant PE; Tao-Cheng JH; Rudow G; Troncoso JC; Liu Z; Li Z; Cai H. 2009. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64(6):807-27. PubMed: 20064389 MGI: J:156512

Additional - Tg(tetO-SNCA*A53T)E2Cai related

Blandini F; Armentero MT. 2012. Animal models of Parkinson's disease. FEBS J 279(7):1156-66. PubMed: 22251459 MGI: J:195105
Chen L; Xie Z; Turkson S; Zhuang X. 2015. A53T human alpha-synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration. J Neurosci 35(3):890-905. PubMed: 25609609 MGI: J:218892
Chen X; Xie C; Sun L; Ding J; Cai H. 2015. Longitudinal Metabolomics Profiling of Parkinson's Disease-Related alpha-Synuclein A53T Transgenic Mice. PLoS One 10(8):e0136612. PubMed: 26317866 MGI: J:243017
Dunn AR; Stout KA; Ozawa M; Lohr KM; Hoffman CA; Bernstein AI; Li Y; Wang M; Sgobio C; Sastry N; Cai H; Caudle WM; Miller GW. 2017. Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease. Proc Natl Acad Sci U S A 114(11):E2253-E2262. PubMed: 28246328 MGI: J:241369
Kim E; Wang B; Sastry N; Masliah E; Nelson PT; Cai H; Liao FF. 2016. NEDD4-mediated HSF1 degradation underlies alpha-synucleinopathy. Hum Mol Genet 25(2):211-22. PubMed: 26503960 MGI: J:229169
Lin X; Parisiadou L; Sgobio C; Liu G; Yu J; Sun L; Shim H; Gu XL; Luo J; Long CX; Ding J; Mateo Y; Sullivan PH; Wu LG; Goldstein DS; Lovinger D; Cai H. 2012. Conditional Expression of Parkinson's Disease-Related Mutant alpha-Synuclein in the Midbrain Dopaminergic Neurons Causes Progressive Neurodegeneration and Degradation of Transcription Factor Nuclear Receptor Related 1. J Neurosci 32(27):9248-64. PubMed: 22764233 MGI: J:185958
Liu G; Yu J; Ding J; Xie C; Sun L; Rudenko I; Zheng W; Sastry N; Luo J; Rudow G; Troncoso JC; Cai H. 2014. Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation. J Clin Invest 124(7):3032-46. PubMed: 24865427 MGI: J:213197
Luo J; Sun L; Lin X; Liu G; Yu J; Parisiadou L; Xie C; Ding J; Cai H. 2014. A calcineurin- and NFAT-dependent pathway is involved in alpha-synuclein-induced degeneration of midbrain dopaminergic neurons. Hum Mol Genet 23(24):6567-74. PubMed: 25051958 MGI: J:216227
Pickrell AM; Huang CH; Kennedy SR; Ordureau A; Sideris DP; Hoekstra JG; Harper JW; Youle RJ. 2015. Endogenous Parkin Preserves Dopaminergic Substantia Nigral Neurons following Mitochondrial DNA Mutagenic Stress. Neuron 87(2):371-81. PubMed: 26182419 MGI: J:227682
Xu J; Wu XS; Sheng J; Zhang Z; Yue HY; Sun L; Sgobio C; Lin X; Peng S; Jin Y; Gan L; Cai H; Wu LG. 2016. alpha-Synuclein Mutation Inhibits Endocytosis at Mammalian Central Nerve Terminals. J Neurosci 36(16):4408-14. PubMed: 27098685 MGI: J:231961

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service	Genotype	Price
	Hemizygous or Non carrier for Tg(tetO-SNCA*A53T)E2Cai

Progeny testing is not required

The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks.

The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.

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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.

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Tg(tetO-SNCA*A53T)E2Cai

Allele Symbol: Tg(tetO-SNCA*A53T)E2Cai

Disease Terms

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Slc6a3tm4.1(tTA)Xz/Slc6a3+ Tg(tetO-SNCA*A53T)E2Cai/0involves: 129S4/SvJaeSor * 129S6/SvEvTac * C57BL/6

nervous system phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

cellular phenotype

Genotype: Tg(Camk2a-tTA)1Mmay/0 Tg(tetO-SNCA*A53T)E2Cai/0involves: C57BL/6

growth/size/body region phenotype

behavior/neurological phenotype

nervous system phenotype

hematopoietic system phenotype

immune system phenotype

cellular phenotype

References

Additional - Tg(tetO-SNCA*A53T)E2Cai related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Progeny testing is not required

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Genotype: Slc6a3^tm4.1(tTA)Xz/Slc6a3⁺ Tg(tetO-SNCAA53T)E2Cai/0
involves: 129S4/SvJaeSor 129S6/SvEvTac * C57BL/6

Genotype: Tg(Camk2a-tTA)1Mmay/0 Tg(tetO-SNCA*A53T)E2Cai/0
involves: C57BL/6