Abstract
Mice heterozygous for the homeobox gene Engrailed-1 (En1) display progressive loss of mesencephalic dopaminergic (mDA) neurons. We report that exogenous Engrailed-1 and Engrailed-2 (collectively Engrailed) protect mDA neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I toxin used to model Parkinson's disease in animals. Engrailed enhances the translation of nuclearly encoded mRNAs for two key complex I subunits, Ndufs1 and Ndufs3, and increases complex I activity. Accordingly, in vivo protection against MPTP by Engrailed is antagonized by Ndufs1 small interfering RNA. An association between Engrailed and complex I is further confirmed by the reduced expression of Ndufs1 and Ndufs3 in the substantia nigra pars compacta of En1 heterozygous mice. Engrailed also confers in vivo protection against 6-hydroxydopamine and Î ±-synuclein- A30P. Finally, the unilateral infusion of Engrailed into the midbrain increases striatal dopamine content, resulting in contralateral amphetamine-induced turning. Therefore, Engrailed is both a survival factor for adult mDA neurons and a regulator of their physiological activity.
| Original language | English |
|---|---|
| Journal | Nature Neuroscience |
| Volume | 14 |
| Issue number | 10 |
| Pages (from-to) | 1260-1266 |
| Number of pages | 7 |
| ISSN | 1097-6256 |
| DOIs | |
| Publication status | Published - 01.10.2011 |
Funding
This work was supported by Agence Nationale pour la Recherche (ANR-06-013-01), the Michael. J. Fox Foundation (MJFF), Fondation de France (Physiopathology of Parkinson disease) and the European Community (FP7 222999, mdDANeurodev project). D.A.-F. was funded by the MJFF, the University Medical Center Giessen and Marburg (UKGM) and the German Academic Exchange Service (DAAD). The CIRB group is part of a Global Research Laboratory (KAIST, South Korea) and a Foundation for Medical Research (FRM) team. J.F. was funded by the German Research Foundation (DFG), the MJFF, FRM and NERF (Neuropôle de Recherche Francilien). A.H. was temporarily supported by INSERM. We thank E. Ipendey for technical help. Confocal imaging and quantification were performed by V. Mignon and B. Saubaméa. We thank the Laboratory of Mass Spectrometry and Proteomics, Institut Curie for assistance. We are indebted to A. Prigent, E. Hirsch, P. Michel and M. Volovitch for intellectual input.
