Mutant huntingtin impairs BDNF release from astrocytes by disrupting conversion of Rab3a-GTP into Rab3a-GDPReportar como inadecuado

Mutant huntingtin impairs BDNF release from astrocytes by disrupting conversion of Rab3a-GTP into Rab3a-GDP - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal Title:

Journal of Neuroscience


Volume 36, Number 34


Society for Neuroscience | 2016-08-24, Pages 8790-8801

Type of Work:

Article | Final Publisher PDF

Abstract: Brain-derived neurotrophic factor BDNF is essential for neuronal differentiation and survival. We know that BDNF levels decline in the brains of patients with Huntington’s disease HD, a neurodegenerative disease caused by the expression of mutant huntingtin protein mHtt, and furthermore that administration of BDNF in HD mice is protective against HD neuropathology. BDNF is produced in neurons, but astrocytes are also an important source of BDNF in the brain. Nonetheless, whether mHtt affects astrocytic BDNF in the HD brain remains unknown. Here we investigated astrocytes from HD140Q knock-in mice and uncovered evidence that mHtt decreases BDNF secretion from astrocytes, which is mediated by exocytosis in astrocytes. Our results demonstrate that mHtt associates with Rab3a, a small GTPase localized on membranes of dense-core vesicles, and prevents GTP-Rab3a from binding to Rab3-GAP1, disrupting the conversion of GTP-Rab3a into GDP-Rab3a and thus impairing the docking of BDNF vesicles on plasma membranes of astrocytes. Importantly, overexpression of Rab3a rescues impaired BDNF vesicle docking and secretion from HD astrocytes. Moreover, ATP release and the number of ATP-containing dense-core vesicles docking are decreased in HD astrocytes, suggesting that the exocytosis of dense-core vesicles is impaired by mHtt in HD astrocytes. Further, Rab3a overexpression reduces reactive astrocytes in the striatum of HD140Q knock-in mice. Our results indicate that compromised exocytosis of BDNF in HD astrocytes contributes to the decreased BDNF levels in HD brains and underscores the importance of improving glial function in the treatment of HD.

Subjects: Biology, Genetics - Biology, Neuroscience - Health Sciences, General - Research Funding: This work was supported by the National Institutes of Health AG19206 and NS041449 to X.-J.L.; AG031153 and NS045016 to S.L

Keywords: BDNF - Huntington's disease - Rab3 - exocytosis - glial cell -

Autor: Yan Hong, Ting Zhao, Xiao-Jiang Li, Shihua Li,



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