G2019S-LRRK2 transgenic mice have a minimal cytomegalovirus (CMV) enhancer and human platelet derived growth factor, B polypeptide (PDGFB) promoter/enhancer elements driving expression of a mutated full length human leucine-rich repeat kinase 2 (LRRK2*G2019S) cDNA. These mice may be useful for studying Parkinson's Disease pathogenesis and neurodegeneration elicited by the dominant toxic effects of mutant LRRK2*G2019S expression.
Valina Dawson, The Johns Hopkins University
Darren J Moore, Van Andel Research Institute
G2019S-LRRK2 transgenic mice have a minimal cytomegalovirus (CMV) enhancer and human platelet derived growth factor, B polypeptide (PDGFB) promoter/enhancer elements driving expression of a mutated full length human leucine-rich repeat kinase 2 (LRRK2*G2019S) cDNA. Hemizygotes are viable, fertile, and normal in size. The LRRK2 cDNA was modified to harbor the LRRK2*G2019S mutation associated with autosomal dominant, late-onset Parkinson's Disease (PD) originally identified in multiple Spanish families and patients with PD. LRRK2 protein, also known as Dardarin, contains multiple functional domains and may play a role in regulating alpha-synuclein-mediated neuropathology through modulating the intracellular trafficking and accumulation of SNCA protein. G2019S-LRRK2 is expressed throughout the olfactory bulb, cerebral cortex, hippocampus, striatum, cerebellum, and neurons of the substantia nigra pars compacta. G2019S-LRRK2 is also overexpressed (2.7-fold over endogenous) within tyrosine hydroxylase (TH)-positive dopaminergic neurons of the substantia nigra pars compacta. These transgenic mice display progressive nigral dopaminergic degeneration, inaddition to reduced complexity of cultured midbrain dopaminergic neurons. They also exhibit enhanced dopamine turnover in the olfactory bulb, as well as autophagic and mitochondrial abnormalities throughout the brain. These mice may be useful for studying PD pathogenesis and neurodegeneration elicited by the dominant toxic effects of mutant LRRK2*G2019S expression.
The G2019S-LRRK2 transgene was designed with a minimal cytomegalovirus (CMV) enhnacer and human platelet derived growth factor, B polypeptide (PDGFB) promoter/enhancer elements driving expression of a full length human leucine-rich repeat kinase 2 (LRRK2) cDNA. LRRK2 cDNA was modified to harbor the LRRK2*G2019S mutation associated with autosomal dominant, late-onset Parkinson's disease. This transgene was microinjected into fertilized (C57BL/6J x C3H/HeJ) F1 oocytes. LRRK2*G2019S mice from founder line 340 were bred to C57BL/6J mice for at least 3 generations. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J mice (Stock No. 000664) for at least one generation to establish the colony.
|Expressed Gene||LRRK2, leucine-rich repeat kinase 2, human|
|Site of Expression|
|Allele Name||transgene insertion 340, Darren Moore|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Gene Symbol and Name||Tg(PDGFB-LRRK2*G2019S)340Djmo, transgene insertion 340, Darren Moore|
|Promoter||PDGFB, platelet-derived growth factor beta polypeptide, human|
|Expressed Gene||LRRK2, leucine-rich repeat kinase 2, human|
|Strain of Origin||(C57BL/6J x C3H/HeJ)F1|
|Mutations Made By|| |
Darren Moore, Van Andel Research Institute
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