ADF-Actin Rods in Neurodegenerative Diseases

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 与年龄相关的神经退行性疾病的始发者。许多老年痴呆症患者 以突触丢失为特征(与年龄相比，丢失高达50% 相关对照)，而神经元丢失是 少得多。某些神经元突起选择性退化的机制 而相关细胞体和其他突起在很大程度上保持完整 无法解释。普乐可复对培养的海马神经元和皮质神经元的作用 神经退行性变的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)/Cofilin-Cortactin-Actin棒。ADF/cofilin是必需的蛋白质， 调节肌动蛋白在体内的周转。通过他们的监管 Lim激酶在单个丝氨酸残基上的磷酸化，ADF/cofilins是一种 肌动蛋白细胞骨架重组信号通路的共同靶点 Rho家族的GTP酶。Cortactin通常与大脑皮层 肌动蛋白是细胞骨架，并受非受体酪氨酸激酶的调节。它有域名 用于结合Arp2/3复合体和Factin，并可能使杆中的细丝交联。 诱导杆状突起的治疗导致ADF/cofilin去磷酸化和至少一个 线粒体的短暂失活。含有ADF的棒状夹杂物是 在阿尔茨海默病大脑中发现：一半的包裹物发生在淀粉样斑块附近， 但是，98%的斑块附近都有含有包裹物的轴突。正常 人类大脑不包含类似的ADF包涵体。生长锥体从 含有宿存杆但正常生长锥体的神经突起在其他 从相同的胞体延伸的过程，证实了持久杆 形成伴随着远端神经突起的变性。 包容性。Rods可能提供了一种机制，将线粒体功能障碍与 选择性修剪突触终末。在这里，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 以下相互关联的假说：在轴突中形成持久杆 突起抑制向该神经突起的远端区域运输。突触 杆远端的过程中的功能将受到损害。淀粉样多肽和 斑块会诱导杆状细胞，因此杆状细胞将在 表达突变淀粉样前体蛋白(APP V717F)的小鼠。棒形编队 需要皮质蛋白去磷酸化和结合Arp2/3的皮质蛋白结构域 复合体和F-肌动蛋白。

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.