Skip to main content
SpringerLink
Log in

Overexpression of α-Synuclein Down-Regulates BDNF Expression

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

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. α-Synuclein has a causal role in Parkinson’s disease, and could interfere with transcriptional regulation of dopamine neurons. In this study, α-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 α-synuclein could associate with protein kinase C (PKC) and impair its activity. Meanwhile glycogen synthase kinase-3β (GSK3β) was activated and extracellular signal-regulated protein kinase (ERK) activity was inhibited by overexpression of α-synuclein; both of them were downstream kinases of PKC. Therefore, the impaired PKC signal pathway caused by α-synuclein overexpression might account at least partially for the down-regulation of BDNF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

BDNF:

Brain-derived neurotrophic factor

NFAT:

Nuclear factor of activated T-cells

MPP+ :

1-Methyl, 4-pheny1, pyridinium

GSK3β:

Glycogen synthase kinase 3β

PD:

Parkinson’s disease

MPTP:

1-Methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine

PKC:

Protein kinase C

CREB:

cAMP response element binding protein

ERK:

Extracellular signal-regulated protein kinases

References

  • Cantuti-Castelvetri I, Keller-McGandy C, Bouzou B, Asteris G, Clark TW, Frosch MP, Standaert DG (2007) Effects of gender on nigral gene expression and Parkinson disease. Neurobiol Dis 26:606–614

    Article  CAS  PubMed  Google Scholar 

  • Fujita M, Sugama S, Nakai M, Takenouchi T, Wei J, Urano T, Inoue S, Hashimoto M (2007) alpha-Synuclein stimulates differentiation of osteosarcoma cells: relevance to down-regulation of proteasome activity. J Biol Chem 282:5736–5748

    Article  CAS  PubMed  Google Scholar 

  • Goers J, Manning-Bog AB, McCormack AL, Millett IS, Doniach S, Di Monte DA, Uversky VN, Fink AL (2003) Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry 42:8465–8471

    Article  CAS  PubMed  Google Scholar 

  • Groth RD, Coicou LG, Mermelstein PG, Seybold VS (2007) Neurotrophin activation of NFAT-dependent transcription contributes to the regulation of pro-nociceptive genes. J Neurochem 102:1162–1174

    Article  CAS  PubMed  Google Scholar 

  • Grunblatt E, Mandel S, Jacob-Hirsch J, Zeligson S, Amariglo N, Rechavi G, Li J, Ravid R, Roggendorf W, Riederer P, Youdim MB (2004) Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. J Neural Transm 111:1543–1573

    Article  CAS  PubMed  Google Scholar 

  • Howells DW, Porritt MJ, Wong JY, Batchelor PE, Kalnins R, Hughes AJ, Donnan GA (2000) Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol 166:127–135

    Article  CAS  PubMed  Google Scholar 

  • Iwata A, Miura S, Kanazawa I, Sawada M, Nukina N (2001) alpha-Synuclein forms a complex with transcription factor Elk-1. J Neurochem 77:239–252

    Article  CAS  PubMed  Google Scholar 

  • Jakes R, Spillantini MG, Goedert M (1994) Identification of two distinct synucleins from human brain. FEBS Lett 345:27–32

    Article  CAS  PubMed  Google Scholar 

  • Johnson A (2009) TNF-induced activation of pulmonary microvessel endothelial cells: a role for GSK3beta. Am J Physiol Lung Cell Mol Physiol 296:L700–L709

    Article  CAS  PubMed  Google Scholar 

  • Kaytor MD, Orr HT (2002) The GSK3b signaling cascade and neurodegenerative disease. Curr Opin Neurobiol 12:275–278

    Article  CAS  PubMed  Google Scholar 

  • Kohno R, Sawada H, Kawamoto Y, Uemura K, Shibasaki H, Shimohama S (2004) BDNF is induced by wild-type alpha-synuclein but not by the two mutants, A30P or A53T, in glioma cell line. Biochem Biophys Res Commun 318:113–118

    Article  CAS  PubMed  Google Scholar 

  • Kontopoulos E, Parvin JD, Feany MB (2006) a-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15:3012–3023

    Article  CAS  PubMed  Google Scholar 

  • Le W-D, Rowe D, Xie W, Ortiz I, He Y, Appel SH (2001) Microglial activation and dopaminergic cell injury: an in vitro model relevant to Parkinson’s disease. J Neurosci 21:8447–8455

    CAS  PubMed  Google Scholar 

  • Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Price DL (2002) Human a-synuclein-harboring familial Parkinson’s disease-linked Ala-53 Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. PNAS 99:8968–8973

    Article  CAS  PubMed  Google Scholar 

  • Leondaritis G, Petrikkos L, Mangoura D (2009) Regulation of the Ras-GTPase activating protein neurofibromin by C-tail phosphorylation: implications for protein kinase C/Ras/extracellular signal-regulated kinase 1/2 pathway signaling and neuronal differentiation. J Neurochem 109:573–583

    Article  PubMed  CAS  Google Scholar 

  • Maher P (2001) How protein kinase C activation protects nerve cells from oxidative stress-induced cell death. J Neurosci 21:2929–2938

    CAS  PubMed  Google Scholar 

  • Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1267

    Article  CAS  PubMed  Google Scholar 

  • Mogi M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, Ichinose H, Nagatsu T (1999) Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson’s disease. Neurosci Lett 270:45–48

    Article  CAS  PubMed  Google Scholar 

  • Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B (1999) alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 19:5782–5791

    CAS  PubMed  Google Scholar 

  • Parain K, Murer MG, Yan Q, Faucheux B, Agid Y, Hirsch E, Raisman-Vozari R (1999) Reduced expression of brain-derived neurotrophic factor protein in Parkinson’s disease substantia nigra. Neuroreport 10:557–561

    Article  CAS  PubMed  Google Scholar 

  • Seroogy KB, Lundgren KH, Tran TM, Guthrie KM, Isackson PJ, Gall CM (1994) Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs. J Comp Neurol 342:321–334

    Article  CAS  PubMed  Google Scholar 

  • Siegel GJ, Chauhan NB (2000) Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain. Brain Res Brain Res Rev 33:199–227

    Article  CAS  PubMed  Google Scholar 

  • Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) a-Synuclein locus triplication causes Parkinson’s disease. Science 302:841

    Article  CAS  PubMed  Google Scholar 

  • Tian L-L, Zhou Z, Zhang Q, Sun Y-N, Li C-R, Cheng C-H, Zhong Z-Y, Wang S-Q (2007) Protective effect of (±) isoborneol against 6-OHDA-induced apoptosis in SH-SY5Y cells. Cell Physiol Biochem 20:1019–1032

    Article  CAS  PubMed  Google Scholar 

  • Tomimatsu N, Arakawa Y (2008) Protein kinase C-mediated protection of motoneurons from excitotoxicity. Neurosci Lett 439:143–146

    Article  CAS  PubMed  Google Scholar 

  • Volakakis N, Malewicz M, Kadkhodai B, Perlmann T, Benoit G (2006) Characterization of the Nurr1 ligand-binding domain co-activator interaction surface. J Mol Endocrinol 37:317–326

    Article  CAS  PubMed  Google Scholar 

  • Volpicelli F, Caiazzo M, Greco D, Consales C, Leone L, Perrone-Capano C, Colucci D’Amato L, di Porzio U (2007) Bdnf gene is a downstream target of Nurr1 transcription factor in rat midbrain neurons in vitro. J Neurochem 102:441–453

    Article  CAS  PubMed  Google Scholar 

  • Xu J, Kao SY, Lee FJ, Song W, Yankner BA (2002) Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med 8:600–606

    Article  CAS  PubMed  Google Scholar 

  • Xu J, Zhong N, Wang H, Elias JE, Kim CY, Woldman I, Pifl C, Gygi SP, Geula C, Yankner BA (2005) The Parkinson’s disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Hum Mol Genet 14:1231–1241

    Article  CAS  PubMed  Google Scholar 

  • Yacoubian TA, Cantuti-Castelvetri I, Bouzou B, Asteris G, McLean PJ, Hyman BT, Standaert DG (2008) Transcriptional dysregulation in a transgenic model of Parkinson disease. Neurobiol Dis 29:515–528

    Article  CAS  PubMed  Google Scholar 

  • Yossifoff M, Kisliouk T, Meiri N (2008) Dynamic changes in DNA methylation during thermal control establishment affect CREB binding to the brain-derived neurotrophic factor promoter. Eur J Neurosci 28:2267–2277

    Article  PubMed  Google Scholar 

  • Yuan Y, Fu C, Chen H, Wang X, Huang B-R (2006) The Ran binding protein RanBPM interacts with TrkA receptor. Neuro Lett 407:26–31

    Article  CAS  Google Scholar 

  • Yuan Y, Yang B, Zhang W, Hu J, Chen NH (2008) Overexpressed alpha-synuclein regulated the nuclear factor-kappaB signal pathway. Cell Mol Neurobiol 28:21–33

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Professor Perlmann from Ludwig Institute for Cancer Research for kindly donating the NBRE3x constructs. This work was supported by National Key Basic Research & Development Program (973 project Grant No. 2004CB518906), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT No.IRT0514), the National Natural Science Foundation of China (No. 30572342 and NO. 30271499) and Special Purpose for New Drug Development (2009ZX09303).

Author information

Authors and Affiliations

  1. 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

    Yuhe Yuan, Jiandong Sun, Ming Zhao, Jinfeng Hu, Xiaoliang Wang, Guohua Du & Nai-Hong Chen

  2. Xuanwu District, Beijing, 100050, China

    Xiaoliang Wang

Authors
  1. Yuhe Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiandong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ming Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jinfeng Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoliang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guohua Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nai-Hong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nai-Hong Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yuan, Y., Sun, J., Zhao, M. et al. Overexpression of α-Synuclein Down-Regulates BDNF Expression. Cell Mol Neurobiol 30, 939–946 (2010). https://doi.org/10.1007/s10571-010-9523-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-010-9523-y

Keywords

Search

Navigation