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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, September 1, 2004, 24(35):7727-7739; doi:10.1523/JNEUROSCI.1197-04.2004

This Article Full Text Full Text (PDF) Supplemental Information 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 (70) Citing Articles via Google Scholar Google Scholar Articles by Canals, J. M. Articles by Alberch, J. Search for Related Content PubMed PubMed Citation Articles by Canals, J. M. Articles by Alberch, J.

 Previous Article  |  Next Article 

Neurobiology of Disease
Brain-Derived Neurotrophic Factor Regulates the Onset and Severity of Motor Dysfunction Associated with Enkephalinergic Neuronal Degeneration in Huntington's Disease

Josep M. Canals,¹ José R. Pineda,¹ Jesús F. Torres-Peraza,¹ Miquel Bosch,¹ Raquel Martín-Ibañez,¹ M. Teresa Muñoz,¹ Guadalupe Mengod,² Patrik Ernfors,³ and Jordi Alberch¹

¹Departament de Biologia Cel·lular i Anatomia Patològica, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, and ²Department of Neurochemistry, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Cientificas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, E-08036 Barcelona, Spain, and ³Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-17177 Stockholm, Sweden

The mechanism that controls the selective vulnerability of striatal neurons in Huntington's disease is unclear. Brain-derived neurotrophic factor (BDNF) protects striatal neurons and is regulated by Huntingtin through the interaction with the neuron-restrictive silencer factor. Here, we demonstrate that the downregulation of BDNF by mutant Huntingtin depends on the length and levels of expression of the CAG repeats in cell cultures. To analyze the functional effects of these changes in BDNF in Huntington's disease, we disrupted the expression of bdnf in a transgenic mouse model by cross-mating bdnf^{+/ -} mice with R6/1 mice. Thus, we compared transgenic mice for mutant Huntingtin with different levels of BDNF. Using this double mutant mouse line, we show that the deficit of endogenous BDNF modulates the pathology of Huntington's disease. The decreased levels of this neurotrophin advance the onset of motor dysfunctions and produce more severe uncoordinated movements. This behavioral pathology correlates with the loss of striatal dopamine and cAMP-regulated phosphoprotein-32-positive projection neurons. In particular, the insufficient levels of BDNF cause specific degeneration of the enkephalinergic striatal projection neurons, which are the most affected cells in Huntington's disease. This neuronal dysfunction can specifically be restored by administration of exogenous BDNF.

Therefore, the decrease in BDNF levels plays a key role in the specific pathology observed in Huntington's disease by inducing dysfunction of striatal enkephalinergic neurons that produce severe motor dysfunctions. Hence, administration of exogenous BDNF may delay or stop illness progression.

Key words: neurotrophins; cell death; striatum; knock-out; movement disorders; polyQ

---

Received March 31, 2004; revised July 1, 2004; accepted July 2, 2004.

This article has been cited by other articles:

				J. Palazuelos, T. Aguado, M. R. Pazos, B. Julien, C. Carrasco, E. Resel, O. Sagredo, C. Benito, J. Romero, I. Azcoitia, et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity Brain, November 1, 2009; 132(11): 3152 - 3164. [Abstract] [Full Text] [PDF]

				M. Diaz-Hernandez, M. Diez-Zaera, J. Sanchez-Nogueiro, R. Gomez-Villafuertes, J. M. Canals, J. Alberch, M. T. Miras-Portugal, and J. J. Lucas Altered P2X7-receptor level and function in mouse models of Huntington's disease and therapeutic efficacy of antagonist administration FASEB J, June 1, 2009; 23(6): 1893 - 1906. [Abstract] [Full Text] [PDF]

				D. del Toro, J. Alberch, F. Lazaro-Dieguez, R. Martin-Ibanez, X. Xifro, G. Egea, and J. M. Canals Mutant Huntingtin Impairs Post-Golgi Trafficking to Lysosomes by Delocalizing Optineurin/Rab8 Complex from the Golgi Apparatus Mol. Biol. Cell, March 1, 2009; 20(5): 1478 - 1492. [Abstract] [Full Text] [PDF]

				H. Seo, W. Kim, and O. Isacson Compensatory changes in the ubiquitin-proteasome system, brain-derived neurotrophic factor and mitochondrial complex II/III in YAC72 and R6/2 transgenic mice partially model Huntington's disease patients Hum. Mol. Genet., October 15, 2008; 17(20): 3144 - 3153. [Abstract] [Full Text] [PDF]

				F. Lazaro-Dieguez, C. Aguado, E. Mato, Y. Sanchez-Ruiz, I. Esteban, J. Alberch, E. Knecht, and G. Egea Dynamics of an F-actin aggresome generated by the actin-stabilizing toxin jasplakinolide J. Cell Sci., May 1, 2008; 121(9): 1415 - 1425. [Abstract] [Full Text] [PDF]

				A. D. Strand, Z. C. Baquet, A. K. Aragaki, P. Holmans, L. Yang, C. Cleren, M. F. Beal, L. Jones, C. Kooperberg, J. M. Olson, et al. Expression Profiling of Huntington's Disease Models Suggests That Brain-Derived Neurotrophic Factor Depletion Plays a Major Role in Striatal Degeneration J. Neurosci., October 24, 2007; 27(43): 11758 - 11768. [Abstract] [Full Text] [PDF]

				D. Rigamonti, D. Bolognini, C. Mutti, C. Zuccato, M. Tartari, F. Sola, M. Valenza, A. G. Kazantsev, and E. Cattaneo Loss of Huntingtin Function Complemented by Small Molecules Acting as Repressor Element 1/Neuron Restrictive Silencer Element Silencer Modulators J. Biol. Chem., August 24, 2007; 282(34): 24554 - 24562. [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]

				V. M. Andre, C. Cepeda, A. Venegas, Y. Gomez, and M. S. Levine Altered Cortical Glutamate Receptor Function in the R6/2 Model of Huntington's Disease J Neurophysiol, April 1, 2006; 95(4): 2108 - 2119. [Abstract] [Full Text] [PDF]

				R. Pardo, E. Colin, E. Regulier, P. Aebischer, N. Deglon, S. Humbert, and F. Saudou Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421 J. Neurosci., February 1, 2006; 26(5): 1635 - 1645. [Abstract] [Full Text] [PDF]

				M. Diaz-Hernandez, J. Torres-Peraza, A. Salvatori-Abarca, M. A. Moran, P. Gomez-Ramos, J. Alberch, and J. J. Lucas Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease J. Neurosci., October 19, 2005; 25(42): 9773 - 9781. [Abstract] [Full Text] [PDF]

				J. Alberch, M. Lopez, C. Badenas, J. L. Carrasco, M. Mila, E. Munoz, and J. M. Canals Association between BDNF Val66Met polymorphism and age at onset in Huntington disease Neurology, September 27, 2005; 65(6): 964 - 965. [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help