B6J.B6N-Snca^{tm3.1(SNCA*E46K)Mdk}/J

Stock number: 039168
Product name: SNCA-GR*E46K
Strain synonyms: E46K SNCA-GR

Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

Humanized E46K SNCA-GR (gene replacement) mice are a knock-in/knock-out model in which the mouse genomic region from Snca (synuclein, alpha) is exchanged for 158 kb of the human SNCA genomic region including the E46K mutation. E46K is associated with Parkinson's disease (PD). This strain may be used to explore more fully the role of SNCA in Parkinson's disease (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and Alzheimer's disease.

Of note, the SNCA-GR model set also includes: B6J.B6N-Snca^{tm1.1(SNCA)Mdk}/J (Stock No. 039166) and B6J.B6N-Snca^{tm2.1(SNCA*A53T)Mdk}/J (Stock No. 039167).

Detailed description

α-Synuclein is a neuronal protein (coded by Snca) which plays a role in synaptic plasticity and neurotransmitter release. Mutations of Snca have been implicated in a group of neurodegenerative diseases that result from an accumulation of α-synuclein in neurons or, in some cases, glial cells. These disorders include Parkinson's disease (PDD), dementia with Lewy bodies (DLB), the Lewy body variant of Alzheimer's disease (AD), multiple system atrophy (MSA), and neurodegeneration with brain iron accumulation.

These humanized E46K SNCA-GR (gene replacement) knock-in/knock-out mice carry a 158 kb fragment of human SNCA replacing the mouse Snca locus and the pathogenic E46K mutation (glutamic acid to lysine) associated with Parkinson's disease and dementia with Lewy bodies. The E46K mutation is the most toxic familial mutation and accelerates the aggregation of ;α-synuclein. Mice homozygous for the mutation are viable and fertile with no obvious phenotype. These mice may be useful for studying SNCA function.

Of note, the SNCA-GR model set also includes: B6J.B6N-Snca^{tm1.1(SNCA)Mdk}/J (Stock No. 039166) and B6J.B6N-Snca^{tm2.1(SNCA*A53T)Mdk}/J (Stock No. 039167).

Development

The E46K SNCA-GR targeting vector was designed to insert a 158 kb (Chr4:89,707,185-89,865,027) fragment of the human SNCA (synuclein, alpha) carrying the E46K (glutamic acid to lysine) mutation in exon 3 in place of Chr6:60,683,985-60,848,702 of the mouse Snca gene on chromosome 6. The genomic sequences are from human assembly GRCh38.p14 and the mouse assembly GRCm39. The construct includes a loxP-flanked neomycin selection cassette. In addition, there is also a SNCA non-coding antisense RNA in the human genome segment. The insertion disrupts Snca transcription. The construct was electroporated into C57BL/6N-PRX-B6N embryonic stem cells (ES). The neomycin cassette was removed by transient expression of Cre. Correctly targeted ES cells were injected into blastocysts. The donating investigator reported that the resultant mice were backcrossed to C57BL/6J mice for at least 5 generations (see SNP note below) prior to sending males to The Jackson Laboratory Repository in 2024. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

In 2024, a high-density single nucleotide polymorphism (~9000 SNP) analysis was performed on the 3 males sent to The Jackson Laboratory. These data support a C57BL/6 genetic background predominantly comprised of C57BL/6J. The existence of the human genomic sequences may contribute to inability of data interpretation to predict percentages.
Of note, the same 3 males were also tested using our routine 48 SNP panel (43 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains). This showed all 48 markers to be C57BL/6J allele-type.

Allele

Symbol: Snca^{tm3.1(SNCA*E46K)Mdk}
Name: targeted mutation 3.1, Michael D Koob
MGI accession ID: MGI:7576960
Generation method: Targeted
Attributes: Null/Knockout; Inserted expressed sequence; Humanized sequence
Synonyms: E46K SNCA-GR
Marker symbol: Snca
Marker name: synuclein, alpha
Marker synonyms: alphaSYN; alpha-Syn; alpha-synuclein; NACP; PARK1; PARK4; PD1
Chromosome: 6
Strain of origin: C57BL/6NTac
Molecular note: The targeting vector is designed to insert a 158 kb (Chr4:89707185 - 89865027) fragment of the human SNCA carrying the E46K (glutamic acid to lysine) mutation in exon 3 in place of Chr6:60683985 - 60848702 of the mouse Snca gene. The genomic sequences are from human assembly GRCh38.p14 and the mouse assembly GRCm39. The construct includes an loxP-flanked neomycin selection cassette. In addition, there is also a SNCA non-coding antisense RNA in the human genome segment. The insertion disrupts Snca transcription.