These transgenic mice carry a humanized synuclein mutant (SNCA*A53T) gene regulated by a tetracycline operator. 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.
Virginia M Lee, University of Pennsylvania
Mice hemizygous for the human synuclein (α-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. α-syn is localized mainly in synapses where it regulates synaptic transmission, neuronal plasticity, synaptic vesicle release, and protein folding. Mutations in α-syn cause autosomal dominantly inherited familial Parkinson's disease (PD) by accelerating 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. Double mutant mice express SNCA two to five fold above the level of endogenous protein, mainly in the forebrain including olfactory bulb, cerebral cortex, hippocampus, subcortical areas after dox administration. They exhibit massive degeneration of postmitotic neurons in the hippocampal dentate gyrus (DG) during postnatal development. 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.
For example, when bred to a strain expressing tTA in forebrain neurons (see Stock No. 003010 for example), this mutant mouse strain may be useful in studies of dementia with Lewy bodies.
A transgene was generated with a A53T mutant α-syn cDNA sequence (encoding a human SNCA*A53T mutant gene) under control of a tetO promoter. The construct was microinjected into (C57BL/6 x C3H)F1 fertilized oocytes, and founder mice were bred to B6C3F1/Crl mice to establish a colony. Upon arrival at The Jackson Laboratory, mice were bred to B6C3F1/J inbred mice (Stock No. 100010) for at least one generation.
|Expressed Gene||SNCA, synuclein alpha, human|
|Site of Expression|
|Allele Name||transgene insertion 33, Virginia M-Y Lee|
|Allele Type||Transgenic (Inducible, Inserted expressed sequence, Humanized sequence)|
|Gene Symbol and Name||Tg(tetO-SNCA*A53T)33Vle, transgene insertion 33, Virginia M-Y Lee|
|Promoter||tetO, tet operator,|
|Expressed Gene||SNCA, synuclein alpha, human|
|Strain of Origin||(C57BL/6 x C3H)F1|
|Molecular Note||This transgene consists of the human alpha-synuclein cDNA encoding a mutated protein with an Ala53Thr mutation under the control of the tetracycline responsive promoter. The mutant alpha-synuclein is expressed only in the presence of the tetracycline transactivator (tTA), expressed from a second transgene; administration of doxycycline inhibits tTA binding to tetO, thus suppressing alpha-synuclein expression.|
|Mutations Made By|| |
Virginia Lee, University of Pennsylvania
When maintained as a live colony, hemizygous mice may be bred to wildtype (non-carrier) mice from the colony or to B6C3F1/J mice (Stock No. 100010).
When using the tetP-A53Talpha-syn (tetP-A53Tα–syn) mouse strain in a publication, please cite the originating article(s) and include JAX stock #016976 in your Materials and Methods section.
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