Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults.

Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 9809671 Publication Model: Electronic Cited Medium: Internet ISSN: 1546-1726 (Electronic) Linking ISSN: 10976256 NLM ISO Abbreviation: Nat Neurosci Subsets: MEDLINE

Publication: <2002->: New York, NY : Nature Publishing Group
Original Publication: New York, NY : Nature America Inc., c1998-

Dopamine/*metabolism ; Homeodomain Proteins/*metabolism ; Mesencephalon/*cytology ; Nerve Tissue Proteins/*metabolism ; Neurons/*physiology ; Neurotoxins/*toxicity; Animals ; Cell Count/methods ; Cells, Cultured ; Chromatography, High Pressure Liquid/methods ; Dizocilpine Maleate/pharmacology ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Electron Transport Chain Complex Proteins/metabolism ; Embryo, Mammalian ; Homeodomain Proteins/pharmacology ; In Vitro Techniques ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; NADH Dehydrogenase/pharmacology ; Nerve Tissue Proteins/pharmacology ; Neurons/drug effects ; Nitro Compounds/toxicity ; Oxidopamine/toxicity ; Propionates/toxicity ; RNA, Small Interfering/pharmacology ; Rotenone/toxicity ; Stereotyped Behavior/drug effects ; Tyrosine 3-Monooxygenase/metabolism ; alpha-Synuclein/metabolism

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 α-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.
(© 2011 Nature America, Inc. All rights reserved.)

Comment in: Nat Neurosci. 2011 Sep 27;14(10):1221-2. doi: 10.1038/nn.2939. (PMID: 21952262)

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0 (Dopamine Plasma Membrane Transport Proteins)
0 (Electron Transport Chain Complex Proteins)
0 (En1 protein, mouse)
0 (Homeodomain Proteins)
0 (Nerve Tissue Proteins)
0 (Neurotoxins)
0 (Nitro Compounds)
0 (Propionates)
0 (RNA, Small Interfering)
0 (alpha-Synuclein)
0 (engrailed 2 protein)
03L9OT429T (Rotenone)
6LR8C1B66Q (Dizocilpine Maleate)
8HW4YBZ748 (Oxidopamine)
EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
EC 1.6.99.3 (NADH Dehydrogenase)
QY4L0FOX0D (3-nitropropionic acid)
VTD58H1Z2X (Dopamine)

Date Created: 20110906 Date Completed: 20111115 Latest Revision: 20211020

20250114

10.1038/nn.2916

21892157