Summary: Researchers have pinpointed a specific marker that contributes to a chronic, but little known, brain condition.
Source: Yale.
A team of researchers led by Yale professor of pathology Wang Min have pinpointed a marker that contributes to a chronic condition affecting the brain..
Known as cerebral cavernous malformations, the condition is characterized by a tangle of capillaries in the brain’s white matter, which can cause headaches, seizures, bleeding, and even death. No effective therapy exists. (It has been reported that Olympic runner Florence Griffith Joyner, who died suddenly in 1998, had this condition.)
Using an animal model of the disease, Min and his co-authors identified a growth factor (angiopoietin-2) that when blocked by an antibody, eliminates the malformations. “We have discovered a new and effective therapy for this potentially debilitating disorder,” he noted.
Source: Ziba Kashef – Yale
Image Source: This NeuroscienceNews.com image is adapted from the Yale press release.
Original Research: Abstract for “Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation” by Huanjiao Jenny Zhou, Lingfeng Qin, Haifeng Zhang, Wenwen Tang, Weidong Ji, Yun He, Xiaoling Liang, Zongren Wang, Qianying Yuan, Alexander Vortmeyer, Derek Toomre, Germaine Fuh, Minghong Yan, Martin S Kluger, Dianqing Wu and Wang Minl in Nature Medicine. Published online August 22 2016 doi:10.1038/nm.4169
[cbtabs][cbtab title=”MLA”]Yale. “Study Uncovers Marker for a Chronic Brain Disease.” NeuroscienceNews. NeuroscienceNews, 23 August 2016.
<https://neurosciencenews.com/brain-disease-bipomarker-4895/>.[/cbtab][cbtab title=”APA”]Yale. (2016, August 23). Study Uncovers Marker for a Chronic Brain Disease. NeuroscienceNews. Retrieved August 23, 2016 from https://neurosciencenews.com/brain-disease-bipomarker-4895/[/cbtab][cbtab title=”Chicago”]Yale. “Study Uncovers Marker for a Chronic Brain Disease.” https://neurosciencenews.com/brain-disease-bipomarker-4895/ (accessed August 23, 2016).[/cbtab][/cbtabs]
Abstract
Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation
Cerebral cavernous malformations (CCMs) are vascular malformations that affect the central nervous system and result in cerebral hemorrhage, seizure and stroke. CCMs arise from loss-of-function mutations in one of three genes: KRIT1 (also known as CCM1), CCM2 or PDCD10 (also known as CCM3). PDCD10 mutations in humans often result in a more severe form of the disease relative to mutations in the other two CCM genes, and PDCD10-knockout mice show severe defects, the mechanistic basis for which is unclear. We have recently reported that CCM3 regulates exocytosis mediated by the UNC13 family of exocytic regulatory proteins. Here, in investigating the role of endothelial cell exocytosis in CCM disease progression, we found that CCM3 suppresses UNC13B- and vesicle-associated membrane protein 3 (VAMP3)-dependent exocytosis of angiopoietin 2 (ANGPT2) in brain endothelial cells. CCM3 deficiency in endothelial cells augments the exocytosis and secretion of ANGPT2, which is associated with destabilized endothelial cell junctions, enlarged lumen formation and endothelial cell–pericyte dissociation. UNC13B deficiency, which blunts ANGPT2 secretion from endothelial cells, or treatment with an ANGPT2-neutralizing antibody normalizes the defects in the brain and retina caused by endothelial-cell-specific CCM3 deficiency, including the disruption of endothelial cell junctions, vessel dilation and pericyte dissociation. Thus, enhanced secretion of ANGPT2 in endothelial cells contributes to the progression of CCM disease, providing a new therapeutic approach for treating this devastating pathology.
“Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation” by Huanjiao Jenny Zhou, Lingfeng Qin, Haifeng Zhang, Wenwen Tang, Weidong Ji, Yun He, Xiaoling Liang, Zongren Wang, Qianying Yuan, Alexander Vortmeyer, Derek Toomre, Germaine Fuh, Minghong Yan, Martin S Kluger, Dianqing Wu and Wang Minl in Nature Medicine. Published online August 22 2016 doi:10.1038/nm.4169
