Reference Report

Reference
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. (Export to RIS)
FlyBase ID	FBrf0207127
Publication Type	Research paper
PubMed ID	18701920
PubMed 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.
DOI	10.1038/emboj.2008.163
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Language of Publication	English
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Parent Publication
Publication Type	Journal
Abbreviation	EMBO J.
Title	The EMBO Journal
Publication Year	1982-
ISBN/ISSN	0261-4189
Data from Reference
Alleles (15)
	eIF-4E⁰⁷²³⁸ eIF-4E^Scer\UAS.cRa Lrrk^3KD.Scer\UAS Lrrk^{dsRNA.Scer\UAS.cIa} Lrrk^{I1915T.Scer\UAS} Lrrk^Scer\UAS.cIa Lrrk^unspecified Lrrk^{Y1383C.Scer\UAS} Scer\GAL4^da.G32 Scer\GAL4^Ddc.PL Scer\GAL4^elav-C155 Scer\GAL4^ple.PF Thor^k13517 Thor^Scer\UAS.cMa Thor^TA.Scer\UAS
Constructs (11)
	P{Ddc-GAL4.L} P{GAL4-da.G32} P{ple-GAL4.F} P{UAS-eIF-4E.R} P{UAS-Lrrk.3KD} P{UAS-Lrrk.I1915T} P{UAS-Lrrk.I} P{UAS-Lrrk.RNAi} P{UAS-Lrrk.Y1383C} P{UAS-Thor.TA} P{UAS-Thor.wt}
Genes (5)
	eIF-4E Lrrk ple Scer\GAL4 Thor
Insertions (1)
	P{GawB}elav^C155
Natural transposons (1)
	P-element