B6N.129S6(Cg)-Atp13a2^tm1Pjsch/J

Stock number: 021914
Research areas: Neurobiology Research

Description

These Atp13a2 targeted mutation mice develop late-onset impaired motor function and behavior, as well as lipofuscinosis. This strain may be useful in studies related to synucleinopathies such as Parkinson's disease, and lysosomal storage disorders.

Detailed description

ATPase type 13A2 belongs to a family of ATPases that transport inorganic cations and other substrates across cell membranes. Certain mutations in the human ATP13A2 gene cause Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis. These mice carry a targeted mutation of the Atp13a2 gene in which exons 12 through 15 and a portion of exon 16 are disrupted by a NEO cassette. Homozygotes are viable and fertile. A truncated transcript is detected by Northern blot and RT-PCR analysis of brain tissue. Western blot analysis did not detect a resultant mutant protein, indicating it is unstable. Homozygotes develop an unsteady gait and reduced spontaneous activity (hindlimb stepping) at 20 months of age. Male homozygotes, between 20 to 29 months of age, display ataxia (uneven stride length). The increased accumulation of intraneuronal storage material (lipofuscin) observed in homozygotes 18-20 months of age was most evident in the hippocampus, where an approximate 3 fold increase in triton-soluble alpha-synuclein is also found. Lipofuscinosis is also found in the cerebellum and cortex. During backcrossing, the Y chromosome may not have been fixed to the C57BL/6NTac genetic background.

Development

A targeting vector designed by Dr. Patrick J. Schultheis (Northern Kentucky University) containing a NEO cassette and polyA sequence was used to disrupt exons 12 through 15 and a portion of exon 16. The construct was electroporated into 129S6/SvEvTac derived CMT1-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were crossed to Black Swiss mice, and then backcrossed to C57BL/6NTac for 8 generations. During backcrossing, the Y chromosome may not have been fixed to the C57BL/6NTac genetic background. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6NJ (Stock No. 005304) at least once to establish the colony.

Allele

Symbol: Atp13a2^tm1Pjsch
Name: targeted mutation 1, Patrick Schultheis
MGI accession ID: MGI:5472135
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Atp13a2
Marker name: ATPase type 13A2
Chromosome: 4
Strain of origin: 129S6/SvEvTac
Molecular note: A targeting vector contains a NEO cassette and polyA sequence that disrupt exons 12 through 15 and a portion of exon 16. Western blot analysis confirmed the absence of protein expression in the brain.