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Título

Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease

Autor Canals, Josep Maria; Pineda, José Ramón; Torres-Peraza, Jesús F.; Bosch, Miquel; Martín-Ibáñez, Raquel; Muñoz, María Teresa; Mengod Los Arcos, Guadalupe ; Ernfors, Patrik; Alberch, Jordi
Palabras clave PolyQ
Striatum
Neurotrophins
Movement disorders
Knock-out
Cell death
Fecha de publicación 1-sep-2004
EditorSociety for Neuroscience
Citación Journal of Neuroscience 24(35): 7727-7739 (2004)
ResumenThe 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.
Versión del editorhttp://dx.doi.org/10.1523/JNEUROSCI.1197-04.2004
URI http://hdl.handle.net/10261/112644
DOI10.1523/JNEUROSCI.1197-04.2004
Identificadoresdoi: 10.1523/JNEUROSCI.1197-04.2004
issn: 0270-6474
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