ADF-Actin Rods in Neurodegenerative Diseases

ADF-肌动蛋白棒在神经退行性疾病中的作用

• 批准号: 6617076
• 负责人: JAMES R BAMBURG
• 金额: $ 1.49万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6617076
• 关键词: actin binding protein; actins; adenosine triphosphate; amyloid proteins; axon; dendrites; electron microscopy; fluorescence microscopy; green fluorescent proteins; human tissue; laboratory mouse; laboratory rat; light microscopy; microfilaments; mitochondrial disease /disorder; neural degeneration; neuritic plaques; neurofibrillary tangles; neuronal transport; neuropathology; phosphorylation; polymerization; protein biosynthesis; protein structure function; synapses; tissue /cell culture

DESCRIPTION (provided by applicant): Microischemia, oxidative stress, and glutamate excitotoxicity are likely initiators of age-related neurodegenerative diseases. Many senile dementias are characterized by a loss of synapses (up to 50 percent loss compared to age related controls) within the hippocampus and cortex, whereas neuronal loss is far less. The mechanism by which some neuronal processes selectively degenerate while associated cell bodies and other processes remain intact is largely unexplained. Treatment of cultured hippocampal and cortical neurons with common mediators of neurodegeneration leads to the formation of axonal and dendritic inclusion bodies in the form of actin depolymerizing factor (ADF)/cofilin-cortactin-actin rods. ADF/cofilins are essential proteins that regulate the turnover of actin in vivo. Through their regulation by phosphorylation on a single serine residue by LIM kinase, ADF/cofilins are a common target of signaling pathways for actin cytoskeletal reorganization via the rho family of GTPases. Cortactin normally associates with the cortical actin cytoskeleton and is regulated by non-receptor tyr kinases. It has domains for binding Arp2/3 complex and Factin and may cross-link filaments in the rods. Treatments that induce rods cause ADF/cofilin dephosphorylation and at least a transient inactivation of mitochondria. Rod-like inclusions containing ADF are found in Alzheimer brain: half of the inclusions occur nearby amyloid plaques, but >98 percent of plaques have neurites nearby that contain inclusions. Normal human brains do not contain similar ADF-inclusions. Growth cones disappear from neurites containing persistent rods but normal growth cones are found on other processes extending from the same soma, confirming that persistent rod formation is accompanied by degeneration of the neurite distal to the inclusion. Rods may provide a mechanism linking mitochondrial dysfunction to the selective pruning of synaptic terminals. Here we propose to determine the role of rods in synapse elimination. Our specific aims are to test the following interrelated hypotheses: Formation of a persistent rod in a neurite process inhibits transport to the distal regions of that neurite. Synaptic function in a process distal to a rod will be impaired. Amyloidpeptides and plaque will induce rods and therefore rods will contribute to the pathology in mice expressing the mutant amyloid precursor protein (APP v717F). Rod formation requires cortactin dephosphorylation and cortactin domains that bind Arp2/3 complex and F-actin.

描述（由申请人提供）： 微缺血、氧化应激和谷氨酸兴奋性毒性可能是 与年龄相关的神经退行性疾病的始作俑者。许多老年痴呆症是 以突触的丧失为特征（与年龄相比， 相关对照），而神经元损失是 一些神经元过程选择性退化的机制 虽然相关的细胞体和其他过程保持完整， 无法解释用普通肝素处理培养的海马和皮层神经元 神经变性介质导致轴突和树突的形成 肌动蛋白解聚因子包涵体 (ADF)/cofilin-coronin-actin杆。ADF/cofilins是必需的蛋白质， 调节体内肌动蛋白的周转。通过他们的监管， 由于LIM激酶对单个丝氨酸残基的磷酸化作用，ADF/cofilins是一种 肌动蛋白细胞骨架重组信号通路的共同靶点， GTP酶的rho家族。皮质蛋白通常与皮质 肌动蛋白细胞骨架，并由非受体酪氨酸激酶调节。它有领域 用于结合Arp 2/3复合物和Factin，并可交联杆中的细丝。 诱导视杆细胞的处理引起ADF/cofilin去磷酸化和至少一种细胞因子。 线粒体的短暂失活。含ADF的棒状包裹体 在阿尔茨海默氏症大脑中发现：一半的内含物发生在淀粉样斑块附近， 但超过98%的斑块附近有含有内含物的神经突。正常 人脑不包含类似的ADF内含物。生长锥消失， 神经突含有持久的杆，但正常的生长锥上发现其他 从同一索马延伸的突起，证实持久杆 形成伴随着神经突远端的变性。 包容。杆可能提供了一种机制，连接线粒体功能障碍， 选择性修剪突触末梢。在这里，我们建议确定 杆在突触消除中的作用。我们的具体目标是测试 以下相互关联的假设：在神经突中形成持久的杆 这个过程抑制了向神经突远端区域的运输。突触 在杆远端的过程中的功能将受到损害。淀粉样肽和 斑块将诱导杆，因此杆将有助于病理学， 表达突变淀粉样前体蛋白（APP v717 F）的小鼠。杆形成 需要皮质蛋白去磷酸化和结合Arp 2/3的皮质蛋白结构域 复合物和F-肌动蛋白。