title: Neuregulin-1 receptor tyrosine kinase ErbB4 is upregulated in midbrain dopaminergic neurons in Parkinson disease.
abstract: Previously we demonstrated that systemically administered neuregulin-1-β1, a nerve growth and differentiation factor, passed the blood-brain barrier and accumulated in brain areas with expression of its receptor ErbB4. In substantia nigra (SN), neuregulin-1-β1 phosphorylated ErbB4 and protected dopaminergic neurons in a toxin-based mouse model of Parkinson disease (PD). We studied ErbB4 in the context of human midbrain dopaminergic degeneration in vivo and in vitro. Post-mortem ventral midbrain tissue sections of neuropsychiatric healthy individuals and PD patients (matched for age, gender and post-mortem delay) were immunostained for ErbB4. Cultured Lund human mesencephalic (LUHMES) post-mitotic dopaminergic neurons were treated with dopaminergic toxins and analyzed for ErbB4 expression. In control individuals, 85.0±5.0% of dopaminergic neurons, containing cytoplasmic neuromelanin, expressed ErbB4 in the SN. In PD cases, the percentage of ErbB4-positive nigral dopaminergic neurons was increased to 94.9±2.5%. The mean ErbB4 immunoreactivity of melanized neurons was higher in PD than controls. LUHMES neurons upregulated ErbB4 when exposed to toxins 1-methyl-4-phenylpyridinium and 6-hydroxydopamine. Increased rate of ErbB4-positive dopaminergic neurons in PD may either reflect a better survival of ErbB4-positive neurons or an increased expression of ErbB4 by remaining neurons to seek trophic support. Enhanced ErbB4 expression in human in vitro toxin-based PD models supports the latter interpretation. Thus, dopaminergic neurons in SN might be susceptible to neuregulin-1 treatment in PD.
authors.affiliation: Department of Neurology, Philipps University, Marburg, Germany. depboylu@med.uni-marburg.de
authors.forename: Candan
authors.initials: C
authors.lastname: Depboylu
authors.forename: Matthias
authors.initials: M
authors.lastname: Höllerhage
authors.forename: Stefan
authors.initials: S
authors.lastname: Schnurrbusch
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
authors.forename: André
authors.initials: A
authors.lastname: Schrattenholz
authors.forename: Günter U
authors.initials: GU
authors.lastname: Höglinger
mesh_terms: D000368:Aged; D015153:Blotting, Western; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000201:enzymology*; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008636:Mesencephalon / Q000201:enzymology*; D010300:Parkinson Disease / Q000201:enzymology*; D066247:Receptor, ErbB-4; D015854:Up-Regulation
chemical_list: C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4