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