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  • The EMBO Journal (2008) 27, 2432 - 2443
  • doi:10.1038/emboj.2008.163

Published online: 14 August 2008

Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila

Yuzuru Imai1, Stephan Gehrke2,3, Hua-Qin Wang4, Ryosuke Takahashi4, Kazuko Hasegawa5, Etsuro Oota6 and Bingwei Lu2,3

  1. Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
  2. Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA
  3. GRECC/VAPAHCS, Palo Alto, CA, USA
  4. Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  5. Department of Neurology, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Japan
  6. Division of Clinical Immunology, Kitasato University Graduate School of Medical Science, Sagamihara, Japan

Correspondence to:

Yuzuru Imai, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-Machi, Aoba-Ku, Sendai, Miyagi 980-8575, Japan. Tel.: +81 22 717 8490; Fax: +81 22 717 8490; E-mail: yimai@idac.tohoku.ac.jp

Bingwei Lu, GRECC/VAPAHCS, 3801 Miranda Ave, Bldg. 100, Palo Alto, CA 94304, USA. Tel.: +650 849 0373; Fax: +650 852 3440; E-mail: bingwei@stanford.edu

Received 31 March 2008; Accepted 25 July 2008

Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent molecular lesions so far found in Parkinson's disease (PD), an age-dependent neurodegenerative disorder affecting dopaminergic (DA) neuron. The molecular mechanisms by which mutations in LRRK2 cause DA degeneration in PD are not understood. Here, we show that both human LRRK2 and the Drosophila orthologue of LRRK2 phosphorylate eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP), a negative regulator of eIF4E-mediated protein translation and a key mediator of various stress responses. Although modulation of the eIF4E/4E-BP pathway by LRRK2 stimulates eIF4E-mediated protein translation both in vivo and in vitro, it attenuates resistance to oxidative stress and survival of DA neuron in Drosophila. Our results suggest that chronic inactivation of 4E-BP by LRRK2 with pathogenic mutations deregulates protein translation, eventually resulting in age-dependent loss of DA neurons.

  • Keywords:

    • 4E-BP,
    • dopaminergic neurodegeneration,
    • LRRK2,
    • Parkinson's disease,
    • protein translation