Dopaminergic Neuronal Loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2

David Ramonet,Rebecca Banerjee,Michael K. Lee,J. Michael McCaffery,Marie Westerlund,M. Flint Beal,Klodjan Stafa,Brian Lin ,Liliane Glauser,Nancy A. Jenkins,Dagmar Galter,Neal G. Copeland,Le Yang ,Ying Liu,Darren J. Moore,Deborah A. Swing,Olga Pletniková ,João Paulo Lima Daher ,Jaekwang Kim,Bobby Thomas,Ted M. Dawson,Valina L. Dawson,Juan C. Troncoso

doi:10.1371/journal.pone.0018568

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.

Highlights

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene (PARK8, OMIM 609007) cause late-onset, autosomal dominant familial Parkinson’s disease (PD) with a clinical and neurochemical phenotype that is largely indistinguishable from sporadic PD [1,2,3]
Our study provides new insight into the pathogenic actions of familial LRRK2 mutations in vivo related to the pathogenesis of PD, and provides a novel model of dopaminergic neurodegeneration induced by the expression of G2019S mutant LRRK2
The expression of full-length human LRRK2 variants was placed under the control of a CMV-enhanced human plateletderived growth factor b-chain (CMVE-PDGFb) promoter (Figure 1A)

Summary

Introduction

Mutations in the LRRK2 gene (PARK8, OMIM 609007) cause late-onset, autosomal dominant familial Parkinson’s disease (PD) with a clinical and neurochemical phenotype that is largely indistinguishable from sporadic PD [1,2,3]. At least six diseasesegregating mutations have been identified in LRRK2-linked families, including the R1441C/G/H, Y1699C, G2019S and I2020T variants [4,5]. LRRK2-linked PD is characterized by the degeneration of substantia nigra dopaminergic neurons and gliosis together with heterogeneous protein inclusion pathology [3,10]. How mutations in LRRK2 precipitate neuronal degeneration and pathology in PD is not known. LRRK2 encodes a multi-domain protein belonging to the ROCO family characterized by a Ras of Complex (ROC) GTPase domain and a C-terminal of ROC (COR) domain in conjunction with a kinase domain with similarity to RIP kinases [11,12].

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Results

Conclusion