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

David Ramonet, João Paulo L Daher, Brian M. Lin, Klodjan Stafa, Jaekwang Kim, Rebecca Banerjee, Marie Westerlund, Olga Pletnikova, Liliane Glauser, Lichuan Yang, Ying Liu, Deborah A. Swing, M. Flint Beal, Juan C Troncoso, J. Michael McCaffery, Nancy A. Jenkins, Neal G. Copeland, Dagmar Galter, Bobby Thomas, Michael K. Lee & 3 others Ted M Dawson, Valina Dawson, Darren J. Moore

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere18568
JournalPLoS One
Volume6
Issue number4
DOIs
StatePublished - 2011

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neurites
Neurites
Leucine
Transgenic Mice
leucine
phosphotransferases (kinases)
Parkinson disease
Phosphotransferases
genetically modified organisms
Parkinson Disease
mutants
mice
Mutation
Dopaminergic Neurons
mutation
Neurons
Bearings (structural)
idiopathic diseases
neurons
Synaptic Transmission

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dopaminergic Neuronal loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2. / Ramonet, David; Daher, João Paulo L; Lin, Brian M.; Stafa, Klodjan; Kim, Jaekwang; Banerjee, Rebecca; Westerlund, Marie; Pletnikova, Olga; Glauser, Liliane; Yang, Lichuan; Liu, Ying; Swing, Deborah A.; Beal, M. Flint; Troncoso, Juan C; McCaffery, J. Michael; Jenkins, Nancy A.; Copeland, Neal G.; Galter, Dagmar; Thomas, Bobby; Lee, Michael K.; Dawson, Ted M; Dawson, Valina; Moore, Darren J.

In: PLoS One, Vol. 6, No. 4, e18568, 2011.

Research output: Contribution to journalArticle

Ramonet, D, Daher, JPL, 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, V & Moore, DJ 2011, 'Dopaminergic Neuronal loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2', PLoS One, vol. 6, no. 4, e18568. https://doi.org/10.1371/journal.pone.0018568
Ramonet, David ; Daher, João Paulo L ; Lin, Brian M. ; Stafa, Klodjan ; Kim, Jaekwang ; Banerjee, Rebecca ; Westerlund, Marie ; Pletnikova, Olga ; Glauser, Liliane ; Yang, Lichuan ; Liu, Ying ; Swing, Deborah A. ; Beal, M. Flint ; Troncoso, Juan C ; McCaffery, J. Michael ; Jenkins, Nancy A. ; Copeland, Neal G. ; Galter, Dagmar ; Thomas, Bobby ; Lee, Michael K. ; Dawson, Ted M ; Dawson, Valina ; Moore, Darren J. / Dopaminergic Neuronal loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2. In: PLoS One. 2011 ; Vol. 6, No. 4.
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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.",
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