B6;129-Lrrk2^tm2.1Shn/J

Stock number: 016209
Research areas: Developmental Biology Research, Endocrine Deficiency Research, Internal/Organ Research, Neurobiology Research

Description

LRRK2 KO1 mice have the promoter and exon 1 of the Lrrk2 gene deleted. These mice may be useful in studying the cellular function of LRRK2 during aging in the maintenance of protein homeostasis.

Detailed description

Mice homozygous for the LRRK2 KO1 mutation are viable and fertile, with the promoter and exon 1 of the Lrrk2 (leucine-rich repeat kinase 2) gene deleted. No mRNA or protein expression from the targeted allele is observed in brain tissues, however a truncated mRNA signal is observed in kidney tissue. Homozygous mice do not exhibit neurodegeneration or neuropathological changes in the brain. In the kidneys, a tissue where LRRK2 is normally expressed at ~6-fold greater levels than brain, homozygous loss of LRRK2 results in renal atrophy by 20 months of age. This is accompanied by significant (~60-fold) age-dependent accumulation of aggregated α-synuclein and ubiquitinated proteins in the kidney. Specifically, homozygous KO kidneys show widely distributed cytosolic α-synuclein-immunoreactive granular aggregates (some amy also contain phospho-Ser-129 α-synuclein) or inclusions in boxy cells of renal tubules in the cortical area by 20 months of age. Other kidney defects observed in homozygous mice include impaired ubiquitin-proteasome system(UPS)-mediated protein degradation, impaired autophagy-lysosomal pathway, increased apoptotic cell death, inflammatory response, and oxidative damage. When combined with a null allele of Lrrk1, it has been reported that double homozygotes exhibit age-dependent loss of dopaminergic neurons and an impairment of the autophagy-lysosomal pathway. These LRRK2 KO1 mice may be useful in studying the cellular function of LRRK2 during aging in the maintenance of protein homeostasis.

Development

A targeting vector was designed to replace the region encompassing the promoter and exon 1 of the Lrrk2 (leucine-rich repeat kinase 2) locus with a loxP-flanked PGK-neo cassette. This construct was electroporated into (C57BL/6 x 129)F1-derived MKV6.5 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. Chimeric mice were bred with B6/129 F1 mice to generate the mutant colony. Next, the mutant mice were bred with CaMKII-Cre transgenic mice on a B6 background. Offspring with the floxed PGK-neo cassette deleted in the germline were bred together (and the CaMKII-Cre transgene was selectively removed) for many generations. Upon arrival at The Jackson Laboratory Repository, mice were bred with B6129SF1/J hybrid mice (Stock No. 101043) for at least one generation to establish the colony.

Allele

Symbol: Lrrk2^tm2.1Shn
Name: targeted mutation 2.1, Jie Shen
MGI accession ID: MGI:4460960
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Lrrk2
Marker name: leucine-rich repeat kinase 2
Chromosome: 15
Strain of origin: (C57BL/6 x 129)F1
Molecular note: The promoter region and exon 1 were replaced with a floxed neo cassette. Cre mediated recombination removed the neo cassette. The absence of protein expression was confirmed by western blot analysis on brain extracts.