Overview

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.

Donating Investigator

Jie Shen, Harvard Med Sch/Brigham Women's Hosp

Genetic overview

Genetic Background	Generation

Lrrk2^tm2.1Shn

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Lrrk2	leucine-rich repeat kinase 2

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Research Applications

Developmental Biology Research
Endocrine Deficiency Research
Internal/Organ Research
Neurobiology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

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.

Control Suggestions

Approximate Controls

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Tong Y; Yamaguchi H; Giaime E; Boyle S; Kopan R; Kelleher RJ 3rd; Shen J. 2010. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of {alpha}-synuclein, and apoptotic cell death in aged mice. Proc Natl Acad Sci U S A 107(21):9879-84PubMed: 20457918 MGI: J:160542

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Genetics

Lrrk2^tm2.1Shn

Allele Symbol: Lrrk2^tm2.1Shn

Allele Name	targeted mutation 2.1, Jie Shen
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Lrrk2^KO1
Gene Symbol and Name	Lrrk2, leucine-rich repeat kinase 2
Gene Synonym(s)
Strain of Origin	(C57BL/6 x 129)F1
Chromosome	15
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.
Mutations Made By	Jie Shen, Harvard Med Sch/Brigham Women's Hosp

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Developmental Biology Research
- Internal/Organ Defects
  - kidney
Endocrine Deficiency Research
- Kidney Defects
Internal/Organ Research
- Kidney Defects
  - lysosomal enzyme abnormalities
Neurobiology Research
- Parkinson's Disease
  - LRRK2 strains

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Lrrk2^tm2.1Shn/Lrrk2^tm2.1Shn
involves: 129 * C57BL/6

cellular phenotype

abnormal autophagy
- at 20 months, kidneys exhibit impaired autophagy-lysosomal pathways compared with wild-type kidneys

increased kidney apoptosis
- at 20 months, kidneys exhibit impaired autophagy-lysosomal pathways compared with wild-type kidneys
- at 20 months, mice exhibit increased apoptosis in the medulla, renal tubules, and glomeruli compared with wild-type mice

increased renal glomerulus apoptosis
- at 20 months

increased renal tubule apoptosis
- at 20 months

renal/urinary system phenotype

abnormal kidney morphology
- at 20 months, kidneys appear rough and granular, are smaller, weigh less, and are darker than in wild-type mice
- at 20 months, kidneys exhibit accumulation and aggregation of alpha-synuclein and ubiquitinated proteins compared with wild-type
- at 20 months, lipofuscin granules accumulate in the kidneys unlike in wild-type mice
- Normal - however, kidneys are normal at 10 weeks

decreased kidney weight
- at 20 months

granular kidney
- at 20 months

increased kidney apoptosis
- at 20 months, kidneys exhibit impaired autophagy-lysosomal pathways compared with wild-type kidneys
- at 20 months, mice exhibit increased apoptosis in the medulla, renal tubules, and glomeruli compared with wild-type mice

increased renal glomerulus apoptosis
- at 20 months

increased renal tubule apoptosis
- at 20 months

kidney atrophy
- in aged mice

kidney inflammation
- at 20 months

small kidney
- at 20 months

homeostasis/metabolism phenotype

abnormal autophagy
- at 20 months, kidneys exhibit impaired autophagy-lysosomal pathways compared with wild-type kidneys

immune system phenotype

kidney inflammation
- at 20 months

mammalian phenotype

nervous system phenotype
- Normal - mice exhibit normal dopaminergic neurons and dopamine turnover

pigmentation phenotype

lipofuscinosis
- at 20 months, lipofuscin granules accumulate in the kidneys unlike in wild-type mice

References

Tong Y; Yamaguchi H; Giaime E; Boyle S; Kopan R; Kelleher RJ 3rd; Shen J. 2010. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of {alpha}-synuclein, and apoptotic cell death in aged mice. Proc Natl Acad Sci U S A 107(21):9879-84PubMed: 20457918 MGI: J:160542

Additional - Lrrk2^tm2.1Shn related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Lrrk2
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, homozygous mice may be bred together.
- Additional Breeding and Husbandry Support
Citation
When using the B6;129-Lrrk2^tm2.1Shn/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #016209 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous for Lrrk2<tm2.1Shn>

Related Products and Services

Frozen Mouse Embryo	B6;129-Lrrk2<tm2.1Shn>/J	$2595.00
Frozen Mouse Embryo	B6;129-Lrrk2<tm2.1Shn>/J	$2595.00
Frozen Mouse Embryo	B6;129-Lrrk2<tm2.1Shn>/J	$3373.50
Frozen Mouse Embryo	B6;129-Lrrk2<tm2.1Shn>/J	$3373.50

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Lrrk2tm2.1Shn

Allele Symbol: Lrrk2tm2.1Shn

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Lrrk2tm2.1Shn/Lrrk2tm2.1Shninvolves: 129 * C57BL/6

cellular phenotype

renal/urinary system phenotype

homeostasis/metabolism phenotype

immune system phenotype

mammalian phenotype

pigmentation phenotype

References

Additional - Lrrk2tm2.1Shn related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Lrrk2^tm2.1Shn

Allele Symbol: Lrrk2^tm2.1Shn

Genotype: Lrrk2^tm2.1Shn/Lrrk2^tm2.1Shn
involves: 129 * C57BL/6

Additional - Lrrk2^tm2.1Shn related