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）： 可能存在微缺血、氧化应激和谷氨酸兴奋毒性 与年龄相关的神经退行性疾病的引发者。许多老年痴呆症是 其特点是突触丧失（与年龄相比损失高达 50%） 海马体和皮质内的相关控制），而神经元损失是 少得多。一些神经元过程选择性退化的机制 而相关的细胞体和其他过程在很大程度上保持完整 无法解释。用常见的方法治疗培养的海马和皮质神经元 神经变性介质导致轴突和树突的形成 肌动蛋白解聚因子形式的包涵体 (ADF)/丝切蛋白-皮质蛋白-肌动蛋白棒。 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 LIM 激酶 ADF/cofilins 对单个丝氨酸残基进行磷酸化 肌动蛋白细胞骨架重组信号通路的共同目标 GTPases 的 rho 家族。 Cortactin 通常与皮质结合 肌动蛋白细胞骨架并受非受体酪氨酸激酶调节。它有域 用于结合 Arp2/3 复合物和肌动蛋白，并且可以交联杆中的细丝。 诱导杆状细胞的治疗会导致 ADF/cofilin 去磷酸化，并且至少 线粒体短暂失活。含有 ADF 的棒状包裹体是 在阿尔茨海默病大脑中发现：一半的内含物出现在淀粉样斑块附近， 但超过 98% 的斑块附近有含有内含物的神经突。普通的 人类大脑不包含类似的 ADF 内含物。生长锥消失 神经突含有持久的杆，但在其他部位发现正常的生长锥 从同一个体细胞延伸出来的过程，证实了持久性杆 形成伴随着神经突远端的​​退化 包容性。杆状体可能提供了一种将线粒体功能障碍与 突触末端的选择性修剪。在此我们建议确定 视杆细胞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杆 该过程抑制了向神经突远端区域的运输。突触 杆远端的过程中的功能将受到损害。淀粉样肽和 斑块会诱发杆状细胞，因此杆状细胞会促进病理学 表达突变淀粉样前体蛋白（APP v717F）的小鼠。杆形成 需要 cortactin 去磷酸化和结合 Arp2/3 的 cortactin 结构域 复合物和F-肌动蛋白。