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Citation
Imai, Y., Gehrke, S., Wang, H.Q., Takahashi, R., Hasegawa, K., Oota, E., Lu, B. (2008). Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila.  EMBO J. 27(18): 2432--2443.
FlyBase ID
FBrf0207127
Publication Type
Research paper
Abstract

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.

PubMed ID
PubMed Central ID
PMC2543051 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    EMBO J.
    Title
    The EMBO Journal
    Publication Year
    1982-
    ISBN/ISSN
    0261-4189
    Data From Reference
    Alleles (15)
    Genes (5)
    Human Disease Models (1)
    Physical Interactions (2)
    Natural transposons (1)
    Insertions (1)
    Experimental Tools (1)
    Transgenic Constructs (11)