title: Overexpression of alpha-synuclein down-regulates BDNF expression.
abstract: Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by the selective loss of nigrostriatal dopaminergic neurons. However, the molecular pathways leading to the dopaminergic neuron degeneration have remained obscure until recently. Reports demonstrated that reduction of brain-derived neurotrophic factor (BDNF) was involved in the etiology and pathogenesis of PD, but its mechanism has not been elucidated. alpha-Synuclein has a causal role in Parkinson's disease, and could interfere with transcriptional regulation of dopamine neurons. In this study, alpha-synuclein overexpression was found to decrease the expression of BDNF, and also to suppress the transactivation of nuclear factors of activated T-cells (NFAT) and cAMP response element binding protein (CREB), both of which regulate BDNF expression. Furthermore, overexpressed alpha-synuclein could associate with protein kinase C (PKC) and impair its activity. Meanwhile glycogen synthase kinase-3beta (GSK3beta) was activated and extracellular signal-regulated protein kinase (ERK) activity was inhibited by overexpression of alpha-synuclein; both of them were downstream kinases of PKC. Therefore, the impaired PKC signal pathway caused by alpha-synuclein overexpression might account at least partially for the down-regulation of BDNF.
authors.affiliation: Key Laboratory of Bioactive Substances and Resources Utilization, Ministry of Education, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
authors.forename: Yuhe
authors.initials: Y
authors.lastname: Yuan
authors.forename: Jiandong
authors.initials: J
authors.lastname: Sun
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Hu
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.forename: Guohua
authors.initials: G
authors.lastname: Du
authors.forename: Nai-Hong
authors.initials: NH
authors.lastname: Chen
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D050778:NFATC Transcription Factors; D051844:alpha-Synuclein; D010768:Phosphoserine; D008156:Luciferases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3
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