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.
Michael K. Lee, University of Minnesota
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.
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. Upon arrival, transgenic mice were additionally bred to C57BL/6J mice to establish the colony.
|Expressed Gene||SNCA, synuclein alpha, human|
|Site of Expression|
|Allele Name||transgene insertion 23, Michael K Lee|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Allele Synonym(s)||A53T-syn; G2-3; Hualpha-Syn(A53T); MoPrP-Hualpha-Syn(A53T); PrPsynA53T; Tg(Prnp-SNCA*A53T)23Dpr|
|Gene Symbol and Name||Tg(Prnp-SNCA*A53T)23Mkle, transgene insertion 23, Michael K Lee|
|Gene Synonym(s)||A53T-syn; G2-3; Hualpha-Syn(A53T); MoPrP-Hualpha-Syn(A53T); PrPsynA53T; Tg(Prnp-SNCA*A53T)23Dpr; Tg(Prnp-SNCA*A53T)23Dpr; transgene insertion 23, Donald L Price|
|Promoter||Prnp, prion protein, mouse, laboratory|
|Expressed Gene||SNCA, synuclein alpha, human|
|Strain of Origin||(C3H/HeJ x C57BL/6J)F1|
|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 transcriptin 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 [
|Molecular Note||The transgene contains a human alpha synuclein cDNA encoding the Ala53Thr amino acid substitution, and the murine prion promoter.|
|Mutations Made By|| |
Michael Lee, University of Minnesota
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.
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