Premium
Phosphorylation of 4E‐BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila
Author(s) -
Imai Yuzuru,
Gehrke Stephan,
Wang HuaQin,
Takahashi Ryosuke,
Hasegawa Kazuko,
Oota Etsuro,
Lu Bingwei
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2008.163
Subject(s) - lrrk2 , biology , eif4e , dopaminergic , microbiology and biotechnology , regulator , translation (biology) , phosphorylation , parkinson's disease , leucine rich repeat , kinase , mutation , genetics , neuroscience , dopamine , gene , disease , medicine , messenger rna
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.