Nucleoskeleton-Cytoskeleton Connections and Cell Polarity in Aging

衰老过程中的核骨架-细胞骨架连接和细胞极性

• 批准号: 10289402
• 负责人: Gregg G Gundersen
• 金额: $ 40.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289402
• 关键词: Actins; Adhesions; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; American; Amyloid beta-Protein; Award; Biological Models; Cell Nucleus; Cell Polarity; Cells; Cellular Morphology; Cerebellar Ataxia; Characteristics; Child; Complex; Cytoskeletal Proteins; Cytoskeleton; Defect; Dementia; Development; Disease; Fibroblasts; Filament; Foundations; Functional disorder; Funding; Generations; Grant; Hippocampus (Brain); Individual; Lead; MAPT gene; Mediating; Microfilaments; Microtubules; Movement; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Neurons; Nuclear; Nuclear Inner Membrane; Nuclear Lamina; Nuclear Outer Membrane; Parents; Pathogenesis; Pathologic; Physiological; Play; Progeria; Proteins; Rattus; Research; Role; Structure; Syndrome; System; Testing; abeta oligomer; aged; cell age; design; druggable target; experimental study; extracellular; hyperphosphorylated tau; migration; neurodegenerative dementia; neuron development; neuron loss; novel; overexpression; parent grant; parent project; tau Proteins; tau aggregation; tau phosphorylation; therapeutic development

SUMMARY The cytoskeleton and its connections to the nucleus play fundamental critical roles in establishing cellular morphology, polarity, migration and substrate adhesion. We have discovered a fundamental cell polarity defect that occurs in physiological aging and in children with the accelerated aging disorder Hutchinson-Gilford progeria syndrome. This defect results from imbalanced connections between the nuclear lamina on the inner aspect of the inner nuclear membrane and two major cytoskeletal protein systems: actin/microfilaments and microtubules. These connections are mediated by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex composed of inner nuclear membrane SUN and outer nuclear membrane KASH proteins. In aging, there is a preferential interaction of increased SUN1 with microtubules versus SUN2 with actin/microfilaments. The parent funded grant (R01 AG064944) for this supplemental application is designed to test the hypothesis that altered nucleocytoskeletal connections mediated by the LINC complex cause an intrinsic cell polarity defect in aging. In this supplement, we will expand the parent project to examine nucleocytoskeletal connections in Alzheimer disease (AD) and related neurodegenerative dementias. The neuronal microtubule-associated protein tau accumulates in a hyperphosphorylated form in neurons in these disorders and amyloid-beta (Aβ) oligomers accumulate extracellularly and induce hyperphosphorylation of tau. We will therefore test the hypothesis that tau and oligomeric Aβ alter microtubule association with LINC complexes and interfere with the generation of cell polarity in a fibroblast model system and in primary neurons. In Aim 1, we will determine if tau and Aβ influence the interactions of microtubules with LINC complexes and alter the generation of cell polarity. To do so, we will use a robust fibroblast model system as proposed in the funded parent award. In Aim 2, we will determine if tau hyperphosphorylation induced by oligomeric Aβ oligomers increases microtubule interactions with the nucleus and perform experiments to establish if these altered interactions underlie concurrent pathological changes in primary neurons. Finally, we will also assess the effects of SUN1 overexpression, which occurs with aging, on primary neurons. This research will implicate tau/Aβ-induced dysfunction of the LINC complex in the pathogenesis of AD and related dementia, and potentially identify targets for the development of therapeutic treatments.

总结 细胞骨架及其与细胞核的连接在建立细胞骨架中起着至关重要的作用。 形态、极性、迁移和基底粘附。我们发现了一个基本的细胞极性缺陷 这发生在生理老化和患有加速老化疾病的儿童中， 综合征这种缺陷是由于细胞核内面核板层之间的不平衡连接造成的。 内核膜和两个主要的细胞骨架蛋白系统：肌动蛋白/微丝和微管。 这些连接是由核骨架和细胞骨架连接体（LINC）复合物介导的 内核膜SUN蛋白和外核膜KASH蛋白。在老龄化方面， 增加的SUN 1与微管相对于SUN 2与肌动蛋白/微丝的相互作用。父母资助的补助金 (R01 AG 064944）旨在检验假设， 由LINC复合物介导的核细胞骨架连接导致衰老中的内在细胞极性缺陷。在 在这篇补充文章中，我们将扩展母项目，研究阿尔茨海默病中的核细胞与骨骼的联系 疾病（AD）和相关的神经退行性痴呆。神经元微管相关蛋白tau 在这些疾病和β淀粉样蛋白（Aβ）寡聚体中， 在细胞外积累并诱导tau的过度磷酸化。因此，我们将测试假设， 和寡聚体Aβ改变微管与LINC复合物的结合并干扰细胞的生成 在成纤维细胞模型系统和原代神经元中的极性。在目标1中，我们将确定tau和Aβ是否影响 微管与LINC复合物的相互作用，并改变细胞极性的产生。为此，我们将 使用一个强大的成纤维细胞模型系统中提出的资助父母奖。在目标2中，我们将确定τ Aβ寡聚体诱导的过度磷酸化增加了微管与细胞核的相互作用 并进行实验，以确定这些改变的相互作用是否是同时发生的病理变化的基础， 初级神经元最后，我们还将评估SUN 1过表达的影响，这与衰老有关， 初级神经元这项研究将涉及tau/Aβ诱导的LINC复合体功能障碍， AD和相关痴呆症的发病机制，并可能确定治疗药物开发的目标 治疗。