title: Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice.
abstract: The homeobox transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dose-dependent manner. Because of this requirement, the cells die by apoptosis when all four alleles of the Engrailed genes are genetically ablated (En1-/-;En2-/-). In the present study, we show that viable and fertile mice, heterozygous null for Engrailed-1 and homozygous null for Engrailed-2 (En1+/-;En2-/-), have an adult phenotype that resembles key pathological features of Parkinson's disease. Specifically, postnatal mutant mice exhibit a progressive degeneration of dopaminergic neurons in the substantia nigra during the first 3 mo of their lives, leading to diminished storage and release of dopamine in the caudate putamen, motor deficits similar to akinesia and bradykinesia, and a lower body weight. This genetic model may provide access to the molecular etiology for Parkinson's disease and could assist in the development of novel treatments for this neurodegenerative disorder.
authors.affiliation: Interdisciplinary Center for Neuroscience, Department of Neuroanatomy, Ruprecht-Karls Universität Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Paola
authors.initials: P
authors.lastname: Sgadò
authors.forename: Lavinia
authors.initials: L
authors.lastname: Albéri
authors.forename: Daniel
authors.initials: D
authors.lastname: Gherbassi
authors.forename: Sherri L
authors.initials: SL
authors.lastname: Galasso
authors.forename: Geert M J
authors.initials: GM
authors.lastname: Ramakers
authors.forename: Kambiz N
authors.initials: KN
authors.lastname: Alavian
authors.forename: Marten P
authors.initials: MP
authors.lastname: Smidt
authors.forename: Richard H
authors.initials: RH
authors.lastname: Dyck
authors.forename: Horst H
authors.initials: HH
authors.lastname: Simon
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D013378:Substantia Nigra / Q000473:pathology* / Q000502:physiology; D000099266:Engrailed 2 Protein
chemical_list: D004298:Dopamine; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000099266:Engrailed 2 Protein; C080330:En1 protein, mouse