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. Although locomotor behavior declines only late in life, and the mice have a normal lifespan, they begin displaying anxiety/depression-like behaviors in middle age.
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. Abnormalities in motor behavior surface with age. While young (two to four months) and middle-aged (10-12 months) mice performed similarly to non-transgenic mice on the Rotarod, older animals (14-18 months) stayed on only about half as long (Lim et al., 2018). Locomotor activity in the open-field test, however, appeared normal at both six and 15 months of age (Ramonet et al., 2011).
As assessed by multiple behavioral tests—including a light-dark test, elevated plus maze, sucrose preference test, forced swimming test, and tail suspension test—LRRK2 G2019S mice develop anxiety/depression-like symptoms at 10-12 months of age (Lim et al., 2018). At the same time, serotonin levels declined in the hippocampus. Moreover, the expression of 5-HT1a receptors ramped up with age in the hippocampus, amygdala, and dorsal raphe nucleus.
At one to two months of age, LRRK2 G2019S mice display normal numbers of neurons in the substantia nigra, as assessed by Nissl staining and TH staining (Ramonet et al., 2011). 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. Elevated levels of the anti-apoptotic proteins, nucleolin and heat-shock protein 70, were observed in whole brains (Jang et al., 2018).
Despite the loss of dopaminergic nigral neurons, the density of TH-positive dopaminergic nerve terminals in the striatum was comparable to the density in non-transgenic mice. Also, levels of striatal dopamine and its primary metabolites were normal even at relatively advanced ages (Ramonet et al., 2011). Specifically, at 14-15 months of age, LRRK2 G2019S mice had wildtype 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-transgenic controls. Moreover, transgenic mice displayed normal pre-pulse inhibition of the acoustic startle reflex, a behavioral measure of sensorimotor gating that can be modulated in part by dopaminergic neurotransmission, at six and 15 months.
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, they exhibited a significant increase in the autophagic vacuoles and abnormally condensed mitochondria in striatal neurons. Mitochondrial volume in striatal microglia was also reduced (Ho et al., 2018). Moreover, brain lysates of four- to six-month-old mice had increased levels of TNF-α and CD68, a marker of microglial activation. Shortening and reduction of microglial processes, typical of microglial activation, were also reported.
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
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.
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.
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 with non-transgenic controls. However, activated microglia were reported in the striatum at 14 months, and CD68 and TNF-α levels were increased in whole brains at 4-6 months.
Increased numbers and condensation of mitochondria in striatal microglia were reported at 14 months. Abnormally high levels of condensed mitochondria were also observed in striatal neurons at 17-18 months.
Rotarod performance deteriorated in 14- to 18-month-old mice. There was no change in pre-pulse inhibition of the acoustic startle reflex.
Anxiety/depression-like symptoms were observed at 10-12 months of age.
Last Updated: 08 Feb 2019
- 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.
- Lim J, Bang Y, Choi JH, Han A, Kwon MS, Liu KH, Choi HJ. LRRK2 G2019S Induces Anxiety/Depression-like Behavior before the Onset of Motor Dysfunction with 5-HT1A Receptor Upregulation in Mice. J Neurosci. 2018 Feb 14;38(7):1611-1621. Epub 2018 Jan 5 PubMed.
- Jang J, Oh H, Nam D, Seol W, Seo MK, Park SW, Kim HG, Seo H, Son I, Ho DH. Increase in anti-apoptotic molecules, nucleolin, and heat shock protein 70, against upregulated LRRK2 kinase activity. Anim Cells Syst (Seoul). 2018;22(5):273-280. Epub 2018 Sep 12 PubMed.
- Ho DH, Je AR, Lee H, Son I, Kweon HS, Kim HG, Seol W. LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation. Exp Neurobiol. 2018 Jun;27(3):171-180. Epub 2018 Jun 30 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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