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: 6826802
• 负责人: JAMES R BAMBURG
• 金额: $ 24.11万
• 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 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826802
• 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）： 微血症，氧化应激和谷氨酸兴奋性可能是可能的 与年龄相关的神经退行性疾病的发起人。许多老年痴呆症是 以突触丧失的特征（与年龄相比，损失高达50％ 在海马和皮质中的相关对照），而神经元的损失为 少得多。某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很大 无法解释。用普通的海马和皮质神经元的治疗 神经变性的介体导致轴突和树突形成 肌动蛋白解聚因子形式的包含体 （ADF）/Cofilin-Cortactin-Actin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激酶对单个丝氨酸残基上的磷酸化，ADF/Cofilins是A 通过 Rho GTPases家族。 Cortactin通常与皮质相关联 肌动蛋白细胞骨架，并由非受体Tyr激酶调节。它有域 用于结合ARP2/3复合物和事实，并且可能在杆上交叉连接丝。 诱导杆引起adf/cofilin dephosphylation的处理和至少A 线粒体的短暂失活。含有ADF的杆状夹杂物是 在阿尔茨海默氏症大脑中发现：一半的夹杂物出现在淀粉样斑块附近， 但是> 98％的斑块附近有包含夹杂物的神经突。普通的 人的大脑不包含类似的ADF嵌入。生长锥从消失 含有持续杆但在其他上发现正常生长锥的神经突 从同一体体延伸的过程，证实了持续的杆 形成伴随着神经突远端的​​变性 包容。杆可以提供将线粒体功能障碍与 突触终端的选择性修剪。在这里，我们建议确定 杆在消除突触中的作用。我们的具体目的是测试 以下相互关联的假设：神经突中持续杆的形成 过程抑制转运到该神经突的远端区域。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 表达突变淀粉样前体蛋白的小鼠（APP V717F）。杆形成 需要结合ARP2/3 复杂和F-肌动蛋白。