Research Models

LRRK2 G2019S Mouse (Tg)

Synonyms: G2019S-LRRK2 (line 340), G2019S-LRRK2 transgenic, LRRK2 G2019S Tg Mouse (Dawson/Moore)

Species: Mouse
Genes: LRRK2
Mutations: LRRK2 G2019S
Modification: LRRK2: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: B6;C3-Tg(PDGFB-LRRK2*G2019S)340Djmo/J
Genetic Background: Transgene introduced into C57BL/6J x C3H/HeJ embryos. Founder mice were bred with C57BL/6J mice.
Availability: Available through The Jackson Laboratory, Stock# 016575, Cryopreserved.

Summary

These transgenic mice overexpress mutant human LRRK2 in the brain. The mutant LRKK2 protein, with the G2019S mutation, is observed throughout the brain, including the striatum, cerebral cortex, hippocampus, cerebellum, and brainstem (Ramonet et al., 2011).

As they age, hemizygous mice develop neurodegeneration of dopaminergic neurons in the substantia nigra, as well as autophagic and mitochondrial abnormalities. Locomotor behavior appears intact and the mice have a normal lifespan.

Hemizygous mice are viable, fertile, and produce normal numbers of progeny. Mutant LRKK2 mRNA is expressed throughout the mouse brain, with the highest expression in the olfactory bulb, cerebral cortex, hippocampus, striatum, and cerebellum. LRRK2 protein was found at levels about 2.7-fold higher than endogenous LRRK2 levels in tyrosine hydroxylase(TH)-positive dopaminergic neurons of the substantia nigra pars compacta.

At one to two months of age, LRRK2 G2019S mice display normal numbers of neurons in the substantia nigra, by Nissl staining and TH staining. But as the mice age, these neurons degenerate. By 19-21 months of age, hemizygous mice exhibit about 18 percent of TH-positive dopaminergic neurons in the substantia nigra pars compacta. There is also a 14 percent reduction in dopaminergic neurons in the substantia nigra pars reticulata. Neuronal numbers in the ventral tegmental area were normal. Despite the loss of dopaminergic nigral neurons, the density of TH-positive dopaminergic nerve terminals in the striatum were comparable to the density in non-Tg mice, suggesting that the remaining dopaminergic neurons were able to compensate.

Despite fewer dopaminergic neurons in the substantia nigra, levels of dopamine and its primary metabolites in the striatum were normal even at relatively advanced ages. Specifically, at 14-15 months of age, LRRK2 G2019S mice had normal levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). In the olfactory bulb, HVA and DOPAC concentrations were low, but dopamine levels were equivalent to non-Tg controls.

The mice were assessed for a variety of neuropathological markers of abnormal protein accumulation and inflammation. Even at advanced ages (23-24 months), the mice did not exhibit abnormalities in α-synuclein, ubiquitin, tau, or GFAP in the ventral midbrain, striatum, or cerebral cortex. However, at 17-18 months of age, the mice exhibited a significant increase in the autophagic vacuoles and abnormal condensed mitchondria in striatal neurons.

Hemizygous mice exhibit no overt behavioral abnormalities up to 24 months of age. In tests of locomotor activity, including the open field quadrant, LRRK2 G2019S mice displayed normal locomotor activity at six and 15 months of age. Similarly, pre-pulse inhibition of the acoustic startle reflex was comparable to non-Tg controls at these ages.

Modification Details

Transgenic mice overexpress full-length mutant human LRRK2 with the G2019S mutation. Transgene expression is driven by a hybrid CMVe-PDGFβ promoter.

Related Strains

LRRK2 G2019S Mouse (Tg) x α-synuclein (A53T) mice -(see Daher et al., 2012).

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Dopamine Deficiency
  • α-synuclein Inclusions
  • Neuroinflammation
  • Motor Impairment

No Data

  • Cognitive Dysfunction

Dopamine Deficiency

At 14-15 months of age, hemizygous mice had normal levels of striatal dopamine, DOPAC, and HVA. However, in the olfactory bulb, levels of HVA and DOPAC were lower, but dopamine was unchanged.

α-synuclein Inclusions

At around 2 years of age, the mice did not exhibit abnormalities in α-synuclein in the ventral midbrain, striatum, or cerebral cortex.

Neuronal Loss

By 19-21 months of age, hemizygous mice lose about 18 percent of TH-positive dopaminergic neurons in the substantia nigra pars compacta and about 14 percent in the substantia nigra pars reticulata. At 1-2 months of age neuronal numbers were normal. The ventral tegmental area did not undergo abnormal neuronal loss.

Neuroinflammation

At around 2 years of age, the mice did not exhibit abnormalities in GFAP in the ventral midbrain, striatum, or cerebral cortex, compared to non-Tg controls.

Motor Impairment

No overt behavioral abnormalities up to 24 months of age. No change in locomotor activity or prepulse inhibition of the acoustic startle reflex.

Mitochondrial Abnormalities

At 17-18 months of age, the hemizygous mice exhibited abnormally high levels of condensed mitochondria in striatal neurons.

Cognitive Dysfunction

No data.

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References

Paper Citations

  1. . Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One. 2011;6(4):e18568. PubMed.
  2. . Neurodegenerative phenotypes in an A53T α-synuclein transgenic mouse model are independent of LRRK2. Hum Mol Genet. 2012 Jun 1;21(11):2420-31. PubMed.

External Citations

  1. The Jackson Laboratory, Stock# 016575

Further Reading

No Available Further Reading