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

  1. Author:
    Ramonet, D.
    Daher, J. P. L.
    Lin, B. M.
    Stafa, K.
    Kim, J.
    Banerjee, R.
    Westerlund, M.
    Pletnikova, O.
    Glauser, L.
    Yang, L. C.
    Liu, Y.
    Swing, D. A.
    Beal, M. F.
    Troncoso, J. C.
    McCaffery, J. M.
    Jenkins, N. A.
    Copeland, N. G.
    Galter, D.
    Thomas, B.
    Lee, M. K.
    Dawson, T. M.
    Dawson, V. L.
    Moore, D. J.

  2. Author Address

    [Ramonet, David; Stafa, Klodjan; Glauser, Liliane; Moore, Darren J.] Ecole Polytech Fed Lausanne, Sch Life Sci, Brain Mind Inst, Lausanne, Switzerland. [Daher, Joao Paulo L.; Lin, Brian M.; Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Inst Cell Engn, NeuroRegenerat Program, Baltimore, MD USA. [Daher, Joao Paulo L.; Lin, Brian M.; Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Stem Cell Program, Baltimore, MD USA. [Daher, Joao Paulo L.; Lin, Brian M.; Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Daher, Joao Paulo L.] Univ Fed Fluminense, Sch Med, Dept Pathol, Niteroi, RJ, Brazil. [Kim, Jaekwang; Pletnikova, Olga; Liu, Ying; Troncoso, Juan C.; Lee, Michael K.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Kim, Jaekwang; Lee, Michael K.] Univ Minnesota, Dept Neurosci, Inst Translat Neurosci, Minneapolis, MN USA. [Banerjee, Rebecca; Yang, Lichuan; Beal, M. Flint; Thomas, Bobby] Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY 10021 USA. [Westerlund, Marie; Galter, Dagmar] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [McCaffery, J. Michael] Johns Hopkins Univ, Integrated Imaging Ctr, Baltimore, MD USA. [McCaffery, J. Michael] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Swing, Deborah A.; Jenkins, Nancy A.; Copeland, Neal G.] NCI, Mouse Canc Genet Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. [Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA.;Ramonet, D, Ecole Polytech Fed Lausanne, Sch Life Sci, Brain Mind Inst, Lausanne, Switzerland.;vdawson@jhmi.edu darren.moore@epfl.ch
    1. Year: 2011
    2. Date: Apr
  2. Journal: Plos One
    1. 6
    2. 4
  4. Type of Article: Article
  5. Article Number: e18568
  6. ISSN: 1932-6203
  1. 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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External Sources

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  2. DOI: 10.1371/journal.pone.0018568
  3. View record in Web of Science®
  4. WOS: 000289192400039

Library Notes

  1. Fiscal Year: FY2010-2011
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