NOTCH3 N-terminal fragmentation in cerebral small vessel disease

脑小血管疾病中的 NOTCH3 N 末端断裂

• 批准号: 10397084
• 负责人: Michael M Wang
• 金额: $ 31.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397084
• 关键词: Acute; Adult; Amino Acids; Arteries; Binding; Biological Models; Blood Vessels; Brain; Brain Diseases; Brain Pathology; CADASIL; Cell Death; Cell Separation; Cerebral small vessel disease; Cessation of life; Chronic; Collagen; Cysteine; Data; Dementia; EGF gene; Generations; In Vitro; Inherited; Lead; Length; Leucine; Microvascular Dysfunction; Mission; Molecular; Molecular Biology; Molecular Conformation; Monoclonal Antibodies; Mus; Mutate; Mutation; N-terminal; NOTCH3 gene; Neurologic; Neurologic Signs; Oxidation-Reduction; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Premature Mortality; Process; Production; Protein Fragment; Proteins; Proteoglycan; Proteolysis; Reagent; Role; Smooth Muscle; Smooth Muscle Myocytes; Stroke; TIMP3 gene; Testing; Transgenic Mice; VWF gene; Vascular Dementia; Vascular Diseases; Vascular Smooth Muscle; base; cell injury; cerebral artery; in vivo; molecular pathology; muscle degeneration; mutant; neuropathology; new therapeutic target; novel; overexpression; role model; therapeutic target; white matter

ABSTRACT Cerebral autosomal dominant arteriopathy with subcortical infarcts leukoencephalopathy (CADASIL) is the most common inherited cause of small vessel disease (SVD), a condition that results in stroke and dementia. Our mission is to understand the molecular pathology of CADASIL in order to define pathways which can be targeted to treat SVD. A majority of CADASIL is caused by cysteine-altering mutations in NOTCH3, suggesting that local redox alteration of the protein is pathogenic. Consequently, altered forms of NOTCH3 may lead to the primary pathological features of CADASIL, which include massive protein accumulation, cell separation, and smooth muscle cell death. In preliminary studies, we identify a novel N-terminal fragment (NTF) of NOTCH3. NTF is a 41 amino acid fragment derived from proteolysis of full-length NOTCH3 that is abundantly expressed in arteries of CADASIL patients. Moreover, NTF is confined to the media of arteries, a region that suffers intense cellular damage in SVD. NTF injected into brains of mice associates with vessels and causes profound small vessels narrowing. Finally, transgenic mice making NTF develop adult onset neurological signs and early death, suggesting the NTF initiates SVD. In this proposal, we hypothesize that NTF is generated by proteolysis of misfolded NOTCH3 and collaborates with full length NOTCH3 to exert neuropathology. Two aims will be pursued: (1) we will characterize the molecular features of NOTCH3 that lead to the generation of NTF, and (2) we will test whether NOTCH3 full length protein is required for NTF to promote SVD of the brain. These studies of CADASIL will potential implicate NTF as a novel pathological protein factor in the genesis of SVD.

摘要 常染色体显性遗传性脑动脉病伴皮质下梗死性白质脑病（CADASIL）是一种 小血管病（SVD）是导致中风和痴呆的最常见遗传原因。 我们的使命是了解CADASIL的分子病理学，以确定可以治疗CADASIL的途径。 用于治疗SVD。大多数CADASIL是由NOTCH 3中的半胱氨酸改变突变引起的， 提示蛋白质的局部氧化还原改变是致病的。因此，改变形式的NOTCH 3 可能导致CADASIL的主要病理特征，包括大量蛋白质积聚、细胞浸润、细胞凋亡和细胞凋亡。 分离和平滑肌细胞死亡。在初步研究中，我们确定了一个新的N-末端片段， (NTF)Notch 3的NTF是来源于全长NOTCH 3的蛋白水解的41个氨基酸片段， 在CADASIL患者的动脉中大量表达。此外，NTF仅限于动脉中膜， 在SVD中遭受严重细胞损伤的区域。神经营养因子注入小鼠脑内与血管相连 并导致深血管狭窄。最后，转基因小鼠的NTF发展成成年发病 神经系统症状和早期死亡，表明NTF启动SVD。在本提案中，我们假设， NTF通过错误折叠的NOTCH 3的蛋白水解产生，并与全长NOTCH 3协同作用， 神经病理学我们将追求两个目标：（1）我们将表征NOTCH 3的分子特征， 导致NTF的产生，以及（2）我们将测试NTF是否需要NOTCH 3全长蛋白， 促进大脑的SVD。CADASIL的这些研究将潜在地暗示NTF作为一种新的病理学 蛋白质因素在SVD的发生。

项目成果

Surge of neurophysiological coupling and connectivity of gamma oscillations in the dying human brain.

• DOI: 10.1073/pnas.2216268120
• 发表时间: 2023-05-09
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Xu, Gang;Mihaylova, Temenuzhka;Li, Duan;Tian, Fangyun;Farrehi, Peter M.;Mashourd, Jack M.;Mashour, George A.;Wang, Michael M.;Borjigin, Jimo
• 通讯作者: Borjigin, Jimo