Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease.
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.
Canals
Josep M
JM
Departament de Biologia Cel.lular i Anatomia Patològica, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Spain.
Pineda
José R
JR
Torres-Peraza
Jesús F
JF
Bosch
Miquel
M
Martín-Ibañez
Raquel
R
Muñoz
M Teresa
MT
Mengod
Guadalupe
G
Ernfors
Patrik
P
Alberch
Jordi
J
D017668:Age of Onset; D000818:Animals; D001259:Ataxia / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use; D016923:Cell Death; D002461:Cell Line, Transformed; D002819:Chorea / Q000235:genetics; D003342:Corpus Striatum / Q000166:cytology; D003433:Crosses, Genetic; D004705:Endocytosis; D004745:Enkephalins / Q000096:biosynthesis / Q000172:deficiency*; D005786:Gene Expression Regulation; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000235:genetics; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology; D014162:Transfection; D018911:Trinucleotide Repeats
D019208:Brain-Derived Neurotrophic Factor; D004745:Enkephalins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins