TY - JOUR
T1 - Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex i insults
AU - Alvarez-Fischer, Daniel
AU - Fuchs, Julia
AU - Castagner, Fraņois
AU - Stettler, Olivier
AU - Massiani-Beaudoin, Olivia
AU - Moya, Kenneth L.
AU - Bouillot, Colette
AU - Oertel, Wolfgang H.
AU - Lombès, Anne
AU - Faigle, Wolfgang
AU - Joshi, Rajiv L.
AU - Hartmann, Andreas
AU - Prochiantz, Alain
PY - 2011/10/1
Y1 - 2011/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80053220669&partnerID=8YFLogxK
U2 - 10.1038/nn.2916
DO - 10.1038/nn.2916
M3 - Journal articles
C2 - 21892157
AN - SCOPUS:80053220669
SN - 1097-6256
VL - 14
SP - 1260
EP - 1266
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 10
ER -
