STOCK Atp13a2^tm1.1Wtd/J

Stock number: 028387
Product name: Atp13a2 floxed
Research areas: Neurobiology Research, Research Tools

Description

Atp13a2 floxed mice have loxP sites flanking exons 2-3 of the Atp13a2 gene. These mice may be useful for studying endolysosomal dysfunction, α-synuclein accumulation, and neurodegeneration associated with the onset of Parkinson’s disease.

Detailed description

Atp13a2 floxed mice have exons 2-3 of the ATPase type 13A2 (Atp13a2) gene flanked by loxP site, ATP13A2 encodes a transmembrane lysosomal ATPase that is involved in intracellular cation homeostasis. Mutations in Atp13a2 have been associated with the onset of Kufor–Rakeb syndrome (KRS), characterized by early-onset Parkinsonism with diffuse cerebral and cerebellar atrophy and neurodegeneration. Homozygotes are viable and fertile. When crossed with a strain expressing Cre Recombinase, resulting offspring will contain a premature stop codon, abolishing gene expression.

Atp13a2 null mice exhibit age-related neuropathological changes, including reactive astrocytosis, lipofuscinosis, protein aggregation, and lysosomal accumulation in multiple brain regions, including the cortex, cerebellum, hippocampus, and striatum by 1 month of age. This was followed by onset of lipofuscinosis and autofluorescence by 3 months of age, and the accumulation of lysosomal proteins LAMP1, LAMP2, and lysosomal lipid BMP by 6 months. The aggregation of ubiquitinated proteins and p62 is evident by 12 months. No α-synuclein related abnormalities are observed in mice up to 18 months of age. Modulating α-synuclein levels by intercrossing these mice with α-synuclein null mice or α-synuclein overexpressing mice (B6;C3-Tg(Prnp-SNCA*A53T)83Vle/J Stock No. 004479) did not change the onset or extent of pathological change.

Development

A targeting vector was designed by Dr. William Dauer (University of Michigan) to insert a loxP site upstream of exon 2 followed by a frt-flanked neomycin resistance (neo) cassette, and a second loxP site downstream of exon 3 of the ATPase type 13A2 (Atp13a2) gene. The construct was electroporated into B6/129 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and resulting chimeric mice were bred with Flp transgenic mice to delete the neo cassette. Resulting progeny were crossed to remove the Flp-expressing transgene. Resulting Atp13a2 null mice were maintained on a mixed B6;129 background. Frozen embryos were recovered to establish our live colony.

Allele

Symbol: Atp13a2^tm1.1Wtd
Name: targeted mutation 1.1, William T Dauer
MGI accession ID: MGI:5779523
Generation method: Targeted
Attributes: Conditional ready (e.g. floxed); No functional change
Synonyms: Apt13a2-flx
Marker symbol: Atp13a2
Marker name: ATPase type 13A2
Marker synonyms: 1110012E06Rik; CLN12; HSA9947; KRPPD; PARK9; RGD1307977; SPG78
Chromosome: 4
Strain of origin: C57BL/6 x 129
Molecular note: A targeting vector was designed to insert a loxP site upstream of exon 2 followed by an FRT-flanked neomycin resistance (neo) cassette, and a second loxP site downstream of exon 3. Flp-mediated recombination removed the FRT-flanked neo cassette.