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Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2004 Sep 01; Vol. 24 (35), pp. 7727-39. - Publication Year :
- 2004
-
Abstract
- 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.
- Subjects :
- Age of Onset
Animals
Ataxia genetics
Brain-Derived Neurotrophic Factor deficiency
Brain-Derived Neurotrophic Factor therapeutic use
Cell Death
Cell Line, Transformed
Chorea genetics
Corpus Striatum cytology
Crosses, Genetic
Endocytosis
Enkephalins biosynthesis
Gene Expression Regulation
Huntingtin Protein
Huntington Disease metabolism
Mice
Mice, Knockout
Mice, Transgenic
Movement Disorders genetics
Nerve Degeneration
Nerve Tissue Proteins deficiency
Nerve Tissue Proteins genetics
Neurons cytology
Neurons metabolism
Nuclear Proteins deficiency
Nuclear Proteins genetics
Phenotype
Stem Cells cytology
Transfection
Trinucleotide Repeats
Brain-Derived Neurotrophic Factor physiology
Enkephalins deficiency
Huntington Disease pathology
Nerve Tissue Proteins physiology
Nuclear Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 24
- Issue :
- 35
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 15342740
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.1197-04.2004