These PAC-Tg(SNCAWT);Snca-/- mice harbor a Snca knock-out allele and a transgene encoding the human α-synuclein. PAC-Tg(SNCAWT);Snca-/- mice are the experimental control for strains that model the very early gastrointestinal dysfunction in the absence of major central nervous system pathology seen in human Parkinson's disease (Stock No. 010788 and Stock No. 010799).
Robert L Nussbaum, University of California San Francisco
These PAC-Tg(SNCAWT);Snca-/- mice are viable and fertile, harboring a Snca knockout allele and a transgene encoding the human α-synuclein. As homozygotes, expression of endogenous mouse α-synuclein is abolished and replaced by human α-synuclein from the two total insertions of the PAC-Tg(SNCAWT). While brain RNA expression of SNCAWT is more than 50-fold greater compared to normal endogenous mouse α-synuclein, protein levels are only 1 to 1.5-fold greater. In colon however, both RNA and protein expression of SNCAWT are ~100-fold greater than normal endogenous mouse α-synuclein. PAC-Tg(SNCAWT);Snca-/- mice do not show any enteric nervous system abnormalities or widespread α-synuclein aggregation in brain or colon. No detectable motor behavior impairments, autonomic abnormalities, olfactory dysfunction, dopaminergic deficits, Lewy body inclusions or neurodegeneration are associated with α-synuclein expression in these mice.
These PAC-Tg(SNCAWT);Snca-/- mice are the experimental control for strains that model the very early gastrointestinal dysfunction in the absence of major central nervous system pathology seen in human Parkinson's disease (Stock No. 010788 and Stock No. 010799).
To generate the PAC-Tg(SNCAWT) transgene, the 146 kb RPCI-1 human male P1 artificial chromosome (PAC) clone 27M07, containing the entire human SNCA (synuclein, alpha (non A4 component of amyloid precursor)) gene and 34 kb of its upstream region, was used. This transgene was microinjected into the pronuclei of fertilized FVB/N ova. The only transgenic founder shown to contain the complete SNCA gene was bred to FVB/N wildtype mice. These PAC-Tg(SNCAWT) transgenic mice were maintained as coisogenic on the FVB/N genetic background by breeding together as homozygotes.
To generate the Snca knockout allele, a targeting vector was designed to replace exons 4 and 5 with a reverse-oriented neomycin resistance cassette (PGK-neo from the vector pPNT). The construct was electroporated into 129S6/SvEvTac-derived TC-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and the resulting mutant mice were generated and maintained as coisogenic on the 129S6/SvEvTac genetic background.
To generate the PAC-Tg(SNCAWT);Snca-/- strain, mice homozygous for the PAC-Tg(SNCAWT) transgene (FVB/N genetic background) were bred with mice homozygous for the Snca knockout allele (129S6/SvEvTac genetic background). Double mutant mice were maintained on a mixed FVB/N;129S6/SvEvTac background using multiple breeding units without repeated brother-sister matings: thus the only portions of the FVB/N or 129S6/SvEvTac genomes fixed in these mice are the FVB/N regions flanking the PAC-Tg(SNCAWT) transgene insertion sites and the 129S6/SvEvTac regions around the Snca knockout allele. These PAC-Tg(SNCAWT);Snca-/- mice were sent to The Jackson Laboratory Repository. Upon arrival, mice were bred together to establish the colony.
|Expressed Gene||SNCA, synuclein alpha, human|
|Site of Expression|
|Allele Name||targeted mutation 1, Robert L Nussbaum|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||Scna-; Snca-|
|Gene Symbol and Name||Snca, synuclein, alpha|
|Gene Synonym(s)||NACP; PARK1; PARK4; PD1; alpha-synuclein; alphaSYN|
|Strain of Origin||129S6/SvEvTac|
|Molecular Note||Exons 4 and 5 were replaced with a neomycin selection cassette inserted by homologous recombination. While the separation of Western blot results by 2D-PAGE showed various isoforms in total brain extract obtained from wild-type mice, protein was undetected in samples obtained from homozygous mutant mice.|
|Allele Name||transgene insertion 1, Robert L Nussbaum|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Allele Synonym(s)||PAC-Tg(SCNAWT); hSNCAWT|
|Gene Symbol and Name||Tg(SNCA)1Nbm, transgene insertion 1, Robert L Nussbaum|
|Promoter||SNCA, synuclein alpha, human|
|Expressed Gene||SNCA, synuclein alpha, human|
|Strain of Origin||FVB/N|
|Molecular Note||To generate the PAC-Tg(SNCAWT) transgene, the 146 kb RPCI-1 human male P1 artificial chromosome (PAC) clone 27M07, containing the entire human SNCA (synuclein, alpha (non A4 component of amyloid precursor)) gene and 34 kb of its upstream region, was used. This transgene was microinjected into the pronuclei of fertilized FVB/N ova. The only transgenic founder shown to contain the complete SNCA gene was bred to FVB/N wildtype mice.|
When maintaining a live colony, mice homozygous for the Snca targeted mutation and homozygous for the Tg(SNCAWT) transgene are bred together. These mice are the experimental control strain for Stock No. 010788 and Stock No. 010799.
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