QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, May 5, 2004, 24(18):4401-4411; doi:10.1523/JNEUROSCI.0348-04.2004

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (153) Citing Articles via Google Scholar Google Scholar Articles by Chen, Z.-Y. Articles by Lee, F. S. Search for Related Content PubMed PubMed Citation Articles by Chen, Z.-Y. Articles by Lee, F. S.

 Previous Article  |  Next Article 

Cellular/Molecular
Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) Alters the Intracellular Trafficking and Activity-Dependent Secretion of Wild-Type BDNF in Neurosecretory Cells and Cortical Neurons

Zhe-Yu Chen,^1,3 Paresh D. Patel,⁴ Gayatree Sant,¹ Chui-Xiang Meng,⁵ Kenneth K. Teng,² Barbara L. Hempstead,² and Francis S. Lee¹

¹Department of Psychiatry and Pharmacology and ²Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, ³Department of Neurobiology, the Second Military Medical University, Shanghai 200433, China, ⁴Mental Health Research Institute and Department of Psychiatry, The University of Michigan Medical School, Ann Arbor, Michigan 48109, and ⁵Department of Basic Medical Sciences, the Second Military Medical University, Shanghai 200433, China

Brain-derived neurotrophic factor (BDNF) plays a critical role in nervous system and cardiovascular development and function. Recently, a common single nucleotide polymorphism in the bdnf gene, resulting in a valine to methionine substitution in the prodomain (BDNF_Met), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders in humans heterozygous for the variant BDNF. When expressed by itself in hippocampal neurons, less BDNF_Met is secreted in an activity-dependent manner. The nature of the cellular defect when both BDNF_Met and wild-type BDNF (BDNF_Val) are present in the same cell is not known. Given that this is the predominant expression profile in humans, we examined the effect of coexpressed BDNF_Met on BDNF_Val intracellular trafficking and processing. Our data indicate that abnormal trafficking of BDNF_Met occurred only in neuronal and neurosecretory cells and that BDNF_Met could alter the intracellular distribution and activity-dependent secretion of BDNF_Val. We determined that, when coexpressed in the same cell, 70% of the variant BDNF forms BDNF_Val·BDNF_Met heterodimers, which are inefficiently sorted into secretory granules resulting in a quantitative decreased secretion. Finally, we determined the form of BDNF secreted in an activity-dependent manner and observed no differences in the forms of BDNF_Met or the BDNF_Val·BDNF_Met heterodimer compared with BDNF_Val. Together, these findings indicate that components of the regulated secretory machinery interacts specifically with a signal in the BDNF prodomain and that perturbations in BDNF trafficking may lead to selective impairment in CNS function.

Key words: brain derived neurotrophic factor; polymorphism; prodomain; proneurotrophin; intracellular trafficking; regulated secretion

---

Received Oct 17, 2003; revised March 23, 2004; accepted March 23, 2004.

This article has been cited by other articles:

				L. Zhao, A.-L. Sheng, S.-H. Huang, Y.-X. Yin, B. Chen, X.-Z. Li, Y. Zhang, and Z.-Y. Chen Mechanism underlying activity-dependent insertion of TrkB into the neuronal surface J. Cell Sci., September 1, 2009; 122(17): 3123 - 3136. [Abstract] [Full Text] [PDF]

				S.-H. Huang, L. Zhao, Z.-P. Sun, X.-Z. Li, Z. Geng, K.-D. Zhang, M. V. Chao, and Z.-Y. Chen Essential Role of Hrs in Endocytic Recycling of Full-length TrkB Receptor but Not Its Isoform TrkB.T1 J. Biol. Chem., May 29, 2009; 284(22): 15126 - 15136. [Abstract] [Full Text] [PDF]

				B. B. Zeev, A. Bebbington, G. Ho, H. Leonard, N. de Klerk, E. Gak, M. Vecksler, and J. Christodoulou The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome Neurology, April 7, 2009; 72(14): 1242 - 1247. [Abstract] [Full Text] [PDF]

				T Foltynie, B Cheeran, C H Williams-Gray, M J Edwards, S A Schneider, D Weinberger, J C Rothwell, R A Barker, and K P Bhatia BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson's disease J. Neurol. Neurosurg. Psychiatry, February 1, 2009; 80(2): 141 - 144. [Abstract] [Full Text] [PDF]

				R. van Winkel, N. C. Stefanis, and I. Myin-Germeys Psychosocial Stress and Psychosis. A Review of the Neurobiological Mechanisms and the Evidence for Gene-Stress Interaction Schizophr Bull, November 1, 2008; 34(6): 1095 - 1105. [Abstract] [Full Text] [PDF]

				O. Bozdagi, E. Rich, S. Tronel, M. Sadahiro, K. Patterson, M. L. Shapiro, C. M. Alberini, G. W. Huntley, and S. R. J. Salton The Neurotrophin-Inducible Gene Vgf Regulates Hippocampal Function and Behavior through a Brain-Derived Neurotrophic Factor-Dependent Mechanism J. Neurosci., September 24, 2008; 28(39): 9857 - 9869. [Abstract] [Full Text] [PDF]

				J. Gardiner, D. Barton, J. May Vanslambrouck, F. Braet, D. Hall, J. Marc, and R. Overall Defects in Tongue Papillae and Taste Sensation Indicate a Problem with Neurotrophic Support in Various Neurological Diseases Neuroscientist, June 1, 2008; 14(3): 240 - 250. [Abstract] [PDF]

				J. Nectoux, N. Bahi-Buisson, I. Guellec, J. Coste, N. D. Roux, H. Rosas, M. Tardieu, J. Chelly, and T. Bienvenu The p.Val66Met polymorphism in the BDNF gene protects against early seizures in Rett syndrome Neurology, May 27, 2008; 70(22_Part_2): 2145 - 2151. [Abstract] [Full Text] [PDF]

				B.-C. Ho, N. C. Andreasen, J. D. Dawson, and T. H. Wassink Association Between Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism and Progressive Brain Volume Changes in Schizophrenia Am J Psychiatry, December 1, 2007; 164(12): 1890 - 1899. [Abstract] [Full Text] [PDF]

				R. Zivadinov, B. Weinstock-Guttman, R. Benedict, M. Tamano-Blanco, S. Hussein, N. Abdelrahman, J. Durfee, and M. Ramanathan Preservation of gray matter volume in multiple sclerosis patients with the Met allele of the rs6265 (Val66Met) SNP of brain-derived neurotrophic factor Hum. Mol. Genet., November 15, 2007; 16(22): 2659 - 2668. [Abstract] [Full Text] [PDF]

				D. Ize-Ludlow, J. A. Gray, M. A. Sperling, E. M. Berry-Kravis, J. M. Milunsky, I. S. Farooqi, C. M. Rand, and D. E. Weese-Mayer Rapid-Onset Obesity With Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Presenting in Childhood Pediatrics, July 1, 2007; 120(1): e179 - e188. [Abstract] [Full Text] [PDF]

				R Huang, J Huang, H Cathcart, S Smith, and S E Poduslo Genetic variants in brain-derived neurotrophic factor associated with Alzheimer's disease J. Med. Genet., February 1, 2007; 44(2): e66 - e66. [Abstract] [Full Text] [PDF]

				D. del Toro, J. M. Canals, S. Gines, M. Kojima, G. Egea, and J. Alberch Mutant huntingtin Impairs the Post-Golgi Trafficking of Brain-Derived Neurotrophic Factor But Not Its Val66Met Polymorphism J. Neurosci., December 6, 2006; 26(49): 12748 - 12757. [Abstract] [Full Text] [PDF]

				J. Gray, G. S.H. Yeo, J. J. Cox, J. Morton, A.-L. R. Adlam, J. M. Keogh, J. A. Yanovski, A. El Gharbawy, J. C. Han, Y.C. L. Tung, et al. Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of the Brain-Derived Neurotrophic Factor (BDNF) Gene Diabetes, December 1, 2006; 55(12): 3366 - 3371. [Abstract] [Full Text] [PDF]

				M. Ito, T. Nagai, H. Kamei, N. Nakamichi, T. Nabeshima, K. Takuma, and K. Yamada Involvement of Tissue Plasminogen Activator-Plasmin System in Depolarization-Evoked Dopamine Release in the Nucleus Accumbens of Mice Mol. Pharmacol., November 1, 2006; 70(5): 1720 - 1725. [Abstract] [Full Text] [PDF]

				Z.-Y. Chen, D. Jing, K. G. Bath, A. Ieraci, T. Khan, C.-J. Siao, D. G. Herrera, M. Toth, C. Yang, B. S. McEwen, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science, October 6, 2006; 314(5796): 140 - 143. [Abstract] [Full Text] [PDF]

				G Oroszi, L Lapteva, E Davis, C H Yarboro, T Weickert, T Roebuck-Spencer, J Bleiberg, D Rosenstein, M Pao, P E Lipsky, et al. The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus Ann Rheum Dis, October 1, 2006; 65(10): 1330 - 1335. [Abstract] [Full Text] [PDF]

				B.-C. Ho, P. Milev, D. S. O'Leary, A. Librant, N. C. Andreasen, and T. H. Wassink Cognitive and Magnetic Resonance Imaging Brain Morphometric Correlates of Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism in Patients With Schizophrenia and Healthy Volunteers. Arch Gen Psychiatry, July 1, 2006; 63(7): 731 - 740. [Abstract] [Full Text] [PDF]

				Z.-Y. Chen, A. Ieraci, M. Tanowitz, and F. S. Lee A Novel Endocytic Recycling Signal Distinguishes Biological Responses of Trk Neurotrophin Receptors Mol. Biol. Cell, December 1, 2005; 16(12): 5761 - 5772. [Abstract] [Full Text] [PDF]

				Z.-Y. Chen, A. Ieraci, H. Teng, H. Dall, C.-X. Meng, D. G. Herrera, A. Nykjaer, B. L. Hempstead, and F. S. Lee Sortilin Controls Intracellular Sorting of Brain-Derived Neurotrophic Factor to the Regulated Secretory Pathway J. Neurosci., June 29, 2005; 25(26): 6156 - 6166. [Abstract] [Full Text] [PDF]

				H. K. Teng, K. K. Teng, R. Lee, S. Wright, S. Tevar, R. D. Almeida, P. Kermani, R. Torkin, Z.-Y. Chen, F. S. Lee, et al. ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTR and Sortilin J. Neurosci., June 1, 2005; 25(22): 5455 - 5463. [Abstract] [Full Text] [PDF]

				R. Blum and A. Konnerth Neurotrophin-Mediated Rapid Signaling in the Central Nervous System: Mechanisms and Functions Physiology, February 1, 2005; 20(1): 70 - 78. [Abstract] [Full Text] [PDF]

				L. Pezawas, B. A. Verchinski, V. S. Mattay, J. H. Callicott, B. S. Kolachana, R. E. Straub, M. F. Egan, A. Meyer-Lindenberg, and D. R. Weinberger The Brain-Derived Neurotrophic Factor val66met Polymorphism and Variation in Human Cortical Morphology J. Neurosci., November 10, 2004; 24(45): 10099 - 10102. [Abstract] [Full Text] [PDF]

				P. T. Pang, H. K. Teng, E. Zaitsev, N. T. Woo, K. Sakata, S. Zhen, K. K. Teng, W.-H. Yung, B. L. Hempstead, and B. Lu Cleavage of proBDNF by tPA/Plasmin Is Essential for Long-Term Hippocampal Plasticity Science, October 15, 2004; 306(5695): 487 - 491. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help