Overexpression of alpha-synuclein down-regulates BDNF expression.
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.
Yuan
Yuhe
Y
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.
Sun
Jiandong
J
Zhao
Ming
M
Hu
Jinfeng
J
Wang
Xiaoliang
X
Du
Guohua
G
Chen
Nai-Hong
NH
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*
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
J Comp Neurol. 1994 Apr 15;342(3):321-34
7912699
Cell Physiol Biochem. 2007;20(6):1019-32
17975304
Hum Mol Genet. 2006 Oct 15;15(20):3012-23
16959795
J Neurochem. 2007 Jul;102(2):441-53
17506860
Science. 2000 Feb 18;287(5456):1265-9
10678833
J Neurochem. 2009 Apr;109(2):573-83
19220708
Neurobiol Dis. 2007 Jun;26(3):606-14
17412603
J Neurochem. 2001 Apr;77(1):239-52
11279280
J Neurosci. 1999 Jul 15;19(14):5782-91
10407019
Biochem Biophys Res Commun. 2004 May 21;318(1):113-8
15110760
Neurosci Lett. 2006 Oct 16;407(1):26-31
16959415
FEBS Lett. 1994 May 23;345(1):27-32
8194594
Am J Physiol Lung Cell Mol Physiol. 2009 Apr;296(4):L700-9
19218353
Neurosci Lett. 2008 Jul 11;439(2):143-6
18514417
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8968-73
12084935
J Mol Endocrinol. 2006 Oct;37(2):317-26
17032747
Science. 2003 Oct 31;302(5646):841
14593171
J Neurosci. 2001 May 1;21(9):2929-38
11312276
Nat Med. 2002 Jun;8(6):600-6
12042811
Curr Opin Neurobiol. 2002 Jun;12(3):275-8
12049933
Cell Mol Neurobiol. 2008 Jan;28(1):21-33
17712623
J Neurosci. 2001 Nov 1;21(21):8447-55
11606633
J Biol Chem. 2007 Feb 23;282(8):5736-48
17189270
Brain Res Brain Res Rev. 2000 Sep;33(2-3):199-227
11011066
Hum Mol Genet. 2005 May 1;14(9):1231-41
15790595
Biochemistry. 2003 Jul 22;42(28):8465-71
12859192
J Neurochem. 2007 Aug;102(4):1162-74
17488277
Eur J Neurosci. 2008 Dec;28(11):2267-77
19046370
Neurosci Lett. 1999 Jul 23;270(1):45-8
10454142
J Neural Transm (Vienna). 2004 Dec;111(12):1543-73
15455214
Neuroreport. 1999 Feb 25;10(3):557-61
10208589
Neurobiol Dis. 2008 Mar;29(3):515-28
18191405
Exp Neurol. 2000 Nov;166(1):127-35
11031089