title: Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2.
abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s) through which familial mutations precipitate neuronal degeneration and PD.
authors.affiliation: Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Ramonet
authors.forename: João Paulo L
authors.initials: JP
authors.lastname: Daher
authors.forename: Brian M
authors.initials: BM
authors.lastname: Lin
authors.forename: Klodjan
authors.initials: K
authors.lastname: Stafa
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Kim
authors.forename: Rebecca
authors.initials: R
authors.lastname: Banerjee
authors.forename: Marie
authors.initials: M
authors.lastname: Westerlund
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.forename: Liliane
authors.initials: L
authors.lastname: Glauser
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Swing
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.forename: J Michael
authors.initials: JM
authors.lastname: McCaffery
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Dagmar
authors.initials: D
authors.lastname: Galter
authors.forename: Bobby
authors.initials: B
authors.lastname: Thomas
authors.forename: Michael K
authors.initials: MK
authors.lastname: Lee
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Moore
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D001343:Autophagy; D001522:Behavior, Animal; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D050505:Mutant Proteins / Q000378:metabolism*; D016501:Neurites / Q000473:pathology* / Q000648:ultrastructure; D009924:Organ Culture Techniques; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport
chemical_list: D050505:Mutant Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine