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.
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.
Transgenic mice overexpress full-length mutant human LRRK2 with the G2019S mutation. Transgene expression is driven by a hybrid CMVe-PDGFβ promoter.
LRRK2 G2019S Mouse (Tg) x α-synuclein (A53T) mice -(see Daher et al., 2012).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Dopamine Deficiency
- α-synuclein Inclusions
- Motor Impairment
- Cognitive Dysfunction
At around 2 years of age, the mice did not exhibit abnormalities in α-synuclein in the ventral midbrain, striatum, or cerebral cortex.
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.
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.
No overt behavioral abnormalities up to 24 months of age. No change in locomotor activity or prepulse inhibition of the acoustic startle reflex.
At 17-18 months of age, the hemizygous mice exhibited abnormally high levels of condensed mitochondria in striatal neurons.
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.
- Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One. 2011;6(4):e18568. PubMed.
- Daher JP, Pletnikova O, Biskup S, Musso A, Gellhaar S, Galter D, Troncoso JC, Lee MK, Dawson TM, Dawson VL, Moore DJ. 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.
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