M83 transgenic mice expresses the mutant human A53T alpha-synuclein under the direction of the mouse prion protein promoter. These mice may be useful in studying human neuronal alpha-synucleinopathies, such as familial Parkinson's Disease.
Virginia M Lee, University of Pennsylvania
Mice homozygous for the transgenic insert are viable and normal in size. These transgenic mice express human A53T variant alpha-synuclein (full-length, 140 amino acid isoform) under the direction of the mouse prion protein promoter. At eight months of age, some homozygous mice develop a progressively severe motor phenotype. Presentation of the phenotype may manifest at 14-15 months of age (on average). Lax grooming, weight loss and diminished mobility precede movement impairment, partial limb paralysis, trembling and inability to stand. Immunohistochemistry analysis of mutants between eight to 12 months of age reveals widely distributed alpha-synuclein inclusions, with dense accumulation in the spinal cord, brainstem, cerebellum and thalamus. The appearance of alpha-synuclein aggregate inclusions parallels the onset of the motor impairment phenotype. Axons and myelin sheaths exhibit progressive ultrastructural degeneration. Immunoelectron microscopy and biochemical analysis show the inclusions in neurons are comprised primarily of 10-16 nm fibrils of alpha-synuclein. The structure, location and onset of the inclusions seen in the mutant mice resemble characteristics seen in human neuronal alpha-synucleinopathies, such as familial Parkinson's Disease. In addition, mice exhibit impaired odor discrimination and detection beginning at 6 months of age. Mice hemizygous for the transgenic insert develop similar phenotypic traits, but onset occurs later, between 22 and 28 months of age. Homozygous mice have a high incidence of nonproductive matings.
A transgenic construct containing the mouse prion protein promoter, its 5' and 3' untranslated regions and human alpha-synuclein A53T mutation cDNA sequence was injected into fertilized B6C3H mouse eggs. Transgenic animals are maintained on a mixed B6C3H background.
|Expressed Gene||SNCA, synuclein, alpha (non A4 component of amyloid precursor), human|
|Site of Expression|
|Allele Name||transgene insertion 83, Virginia M-Y Lee|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Allele Synonym(s)||A53T alpha-synuclein PRP; M83; PrP-alpha-syn mice (line M83); Prp-alphaSynA53T; Tg(SNCA)83Vle; alphaS+|
|Gene Symbol and Name||Tg(Prnp-SNCA*A53T)83Vle, transgene insertion 83, Virginia M-Y Lee|
|Gene Synonym(s)||A53T alpha-synuclein PRP; M83; Tg(SNCA)83Vle; Tg(SNCA)83Vle; alphaS+|
|Promoter||Prnp, prion protein, mouse, laboratory|
|Expressed Gene||SNCA, synuclein, alpha (non A4 component of amyloid precursor), human|
|Strain of Origin||C57BL/6 x C3H|
|Mutations Made By|| |
John Trojanowski, Dept. Pathology and Laboratory Med
The strain is maintained as a hemizygote on the same background. Homozygous mice have a high incidence of nonproductive matings. Coat color expected from breeding is Agouti.
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