Nuclear and Glial Dysfunction in Neurodegeneration

神经退行性变中的核和神经胶质功能障碍

• 批准号: 10664230
• 负责人: Jeffrey D Rothstein
• 金额: $ 122.81万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2031-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664230
• 关键词: ALS patients; Aging; Astrocytes; Biological Models; Biology; C9ALS; C9ORF72; Cell Line; Cellular biology; Data; Defect; Degenerative Disorder; Dementia; Dendrites; Development; Disease; Disease Marker; Drosophila genus; Educational process of instructing; Elements; Functional disorder; Future; Health; Human; Huntington Disease; Induced pluripotent stem cell derived neurons; Injury; Learning; Link; Location; Modeling; Motor Neurons; Mutation; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Neurons; Nuclear; Nuclear Pore; Nuclear Pore Complex; Pathogenicity; Pathology; Pathway interactions; Patients; Process; Property; Proteins; Rodent; Subgroup; Synapses; System; Therapeutic; Validation; Vertebral column; brain tissue; candidate identification; cell type; drug action; drug discovery; fly; frontotemporal lobar dementia amyotrophic lateral sclerosis; human disease; in vivo; induced pluripotent stem cell; insight; loss of function; molecular subtypes; mouse model; mutant; novel therapeutics; nucleocytoplasmic transport; protein TDP-43; repaired; sporadic amyotrophic lateral sclerosis; therapeutic candidate; tool

Abstract In the last 5–10-years new model systems, to study ALS, FTD and other dementias, based on patient derived induced pluripotent cell lines have provide great insight into highly relevant disease-causing pathways as well as fundamental neuronal and glial cell biology. New studies using these, and other model systems suggest the nuclear transport is the fundamental injury linked to both familial sporadic ALS and FTD. Emerging studies now implicate nuclear transport and the nuclear pore complex in multiple different neurodegenerative diseases including ALS, FTD, Huntington’s disease and even aging. These studies are beginning to identify candidate therapies for sporadic forms of the disease. The nuclear pore complex is diverse, and mutations of its constituent proteins can lead to a wide range of different degenerative diseases. Thus, studies of the CNS nuclear pore and nucleocytoplasmic transport have pathogenic implications that are wide ranging. This proposal will comprehensively investigate the biology of CNS nuclear pores and nuclear transport- the fundamental properties in different neuronal and glia, mechanisms by which the nuclear pore is disrupted, include possibly disease initiating biology involving the ESCT3/CHMP7 pathways, how the nuclear pore complex is disrupted in sporadic and familial forms of the diseases utilizing several complementary models including C9-ALS fly and mouse models and iPS neurons and brain tissue from sporadic and C9orf72 mutant ALS/FTD patients. We will also investigate whether modulation of nucleocytoplasmic transport and /or repair of the nuclear pore complex may be a therapeutic strategy for ALS/FTD. Our emerging data teach that there are multiple candidate therapeutic opportunities for this pathway and neurodegeneration. As we have now learned that defect on the nuclear pore complex are upstream of the disruption of TDP43 nuclear location and loss of function, this pathway may have relevance to not only ALS and FTD – but other neurological injuries involving TDP43 misregulation. Finally, studies over the last decade have revealed that neurodegenerative diseases are not simply a disorder of neurons, but that glial cells also contribute to pathophysiology. Many studies have implicated aberrant astroglial function in ALS and neurodegeneration. Regional alterations of astroglia have long been known—but how this occurs and whether astroglia exist as functional/molecular subtypes has been unclear. New studies from our group and others now suggests real subtypes of astroglia exist, may have specific functions n modulating cortical dendritic and synaptic biology and may be selectively altered in ALS. The biology of these newly identified subgroups will be explored in this proposal and how they alter spines/dendrites, neuronal elements known to be dramatically altered in neurodegeneration.

摘要 在最近5-10年的新模型系统中，研究ALS、FTD和其他痴呆，基于患者推导 诱导多能细胞系也为高度相关的致病途径提供了很好的见解 作为神经元和神经胶质细胞生物学的基础。使用这些模型和其他模型系统的新研究表明， 核转运是与家族性散发性ALS和FTD相关的基本损伤。新兴 现在的研究表明，核转运和核孔复合体在多种不同的神经退行性疾病中， 包括ALS、FTD、亨廷顿氏病甚至衰老在内的疾病。这些研究开始发现 用于散发形式的疾病的候选疗法。核孔复合体是多样的， 其组成蛋白质可导致多种不同的退行性疾病。因此，CNS的研究 核孔和核质运输具有广泛的致病性。这 该提案将全面研究CNS核孔和核运输的生物学- 不同神经元和神经胶质的基本特性，核孔被破坏的机制， 包括可能涉及ESCT 3/CHMP 7途径的疾病引发生物学，核孔如何 利用几种互补模型， 包括C9-ALS苍蝇和小鼠模型以及来自散发性和C9 orf 72突变体的iPS神经元和脑组织 ALS/FTD患者。我们还将研究是否调节核质转运和/或修复 核孔复合物的形成可能是ALS/FTD的治疗策略。我们的新数据表明， 是该途径和神经变性的多种候选治疗机会。就像我们现在一样 了解到核孔复合物上缺陷是TDP 43核定位破坏的上游， 功能丧失，该通路可能不仅与ALS和FTD相关，而且与其他神经损伤相关 涉及TDP 43失调。最后，过去十年的研究表明， 疾病不仅仅是神经元的紊乱，神经胶质细胞也参与了病理生理学。许多 研究表明ALS和神经变性中存在异常的星形胶质细胞功能。区域变化 星形胶质细胞早已被人们所知，但这是如何发生的，以及星形胶质细胞是否作为功能/分子存在 亚型尚不清楚。我们小组和其他人的新研究现在提出了星形胶质细胞的真实的亚型 存在，可能具有调节皮质树突和突触生物学的特定功能，并且可能选择性地 在ALS中改变。这些新发现的亚群的生物学将在本提案中进行探讨，以及它们是如何 改变棘/树突，已知在神经变性中显著改变的神经元元件。