"A Novel Role for the UPR Component, ATF6 in AD-associated Neuroprotective Pathways"

“UPR 成分 ATF6 在 AD 相关神经保护途径中的新作用”

基本信息

批准号：
10353397
负责人：
Timothy Yikai Huang
金额：
$ 97.48万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10353397
关键词：
ATF6 gene Acute Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid Amyloid Fibrils Amyloid beta-Protein Amyloid deposition Astrocytes Attenuated Behavior Behavioral Bioenergetics Bipolar Disorder Brain Cell Death Cell Survival Cells Chinese population Chronic Cognition Cognitive Cognitive deficits Collection Color blindness Complex Data Defect Dementia Deposition Development Disease Disease Progression Electrophysiology (science)Endoplasmic Reticulum Enterobacteria phage P1 Cre recombinase Event Functional disorder GRP78 gene GRP94 Gene Expression Genetic Models Genetic Polymorphism Genetic Transcription Golgi Apparatus Grant Hippocampus (Brain)Human Immunohistochemistry Impaired cognition Impairment Individual Induced pluripotent stem cell derived neurons Inositol Link Measures Mediating Memory Messenger RNA Metabolism Microglia Molecular Chaperones Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Neurophysiology - biologic function Nuclear Translocation Onset of illness Organoids Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacology Phenotype Phosphorylation Phosphotransferases Physiological Production Promoter Regions Property Proteins RNA Splicing Reporting Retina Retinal Cone Role Senile Plaques Signal Pathway Signal Transduction Stress Sum Synapses Synaptic Potentials Synaptic plasticity Tamoxifen Testing Thinness Transgenic Mice Transgenic Organisms Variant Vertebral column XBP1 gene abeta accumulation abeta oligomer achromatopsia activating transcription factor age related arm behavioral phenotyping brain tissue cell type cognitive function density endoplasmic reticulum stress extracellular gain of function improved insight loss of function mRNA Expression mRNA sequencing misfolded protein mouse model neuron development neuron loss neuroprotection novel prevent protein degradation protein expression protein folding protein misfolding proteostasis proteotoxicity response sensor small molecule synaptic function tau Proteins tau aggregation tool transcription factor

项目摘要

PROJECT SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia, characterized by misfolding and aggregation of specific proteins which manifest in pathological features including neuronal loss, cognitive decline and histopathological hallmarks such as the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Amyloid plaques comprise extracellular deposits of amyloid-b (Ab) aggregates, where Aβ oligomers are thought to be proteotoxic to neuronal function. Numerous studies have demonstrated that AD-associated proteotoxicity triggers an adaptive unfolded protein response (UPR) which attempts to restore proteostatic dysfunction due to accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR signaling is mediated through PERK/eIF2a, IRE1/XBP1, and ATF6 sensor pathways; relative contributions of these signaling arms to neurodegeneration is complex as they have dual roles in mediating cell survival and cell death. Elevations in PERK/phosphorylated eIF2a, XBP1 mRNA splicing, and increased levels of ER chaperones such as BiP/GRP78, GRP94 and PDI in human AD brain strongly suggests chronic activation of ER stress is evident in human AD pathology. Further, a polymorphism previously linked to bipolar disorders within the XBP1 promoter region was linked to increased AD risk in Chinese populations. Although it has been established that UPR pathways are activated in disorders such as AD, it is not clear whether UPR pathways confer neuroprotective effects, or if their activation can contribute to pathogenesis. Potential neuroprotective effects of the ATF6 pathway in neurodegeneration have remained particularly elusive. ATF6 functions as an ER stress sensor and transcription factor that promotes expression of genes that enhance proper protein folding via increased production of ER chaperones and increased degradation of misfolded proteins. We present new evidence that ATF6 is essential for synaptic function, as Atf6-/- mice display cognitive and behavioral defects associated with reduced synaptic spine density. Further, exogenous expression of the active ATF6 form suppressed accumulation of amyloid fibrils in a murine model of AD. These results provide strong evidence that ATF6 activation may have a physiological role in synaptic activity and cognitive behavior, and acute ATF6 activation can confer neuroprotective effects with AD-associated proteotoxicity. In the proposed study, our efforts will be focused on elucidating potential neuroprotective effects of ATF6 on neuronal and synaptic function, and differentiate potential roles for ATF6 in neurons and microglia. Given the effects of ATF6 on attenuating Aβ plaque formation, we will characterize proteins that are particularly susceptible to proteostatic dysfunction in AD. We will also characterize the effects of ATF6 mutational variants identified in human Achromatopsia patients on neuronal function, and determine whether pharmacological activation of ATF6 is protective in AD. The sum of these results will implicate a novel role for ATF6 in neuronal/synaptic function, and provide insight into potential strategies to reverse synaptic impairment through enhancing UPR function.

项目摘要阿尔茨海默氏病（AD）是痴呆症的最常见形式，其特征是错误形式和特定蛋白质的聚集在病理特征中表现出包括神经元丧失，认知能力下降以及组织病理学的标志，例如淀粉样蛋白斑块的积累和神经著名缠结大脑。许多研究表明，这是相关的蛋白毒素触发自适应展开的蛋白质反应（UPR），该蛋白质反应试图恢复蛋白抑制剂由于内质网（ER）中错误折叠蛋白的积累而引起的功能障碍介导的Throgh Perk/EIF2A，IRE1/XBP1和ATF6传感器途径；神经变性的臂很复杂，因为它们在介导细胞存活和细胞死亡中具有双重作用。 PERK/PERK/磷酸化EIF2A，XBP1 mRNA剪接和ER伴侣水平的升高正如BIP/GRP78一样在人类AD病理学中，多态性先前与XBP1启动子中区域与中国人口的AD风险增加有关。途径在AD等疾病中被激活，尚不清楚UPR途径是否赋予神经保护作用影响，或者它们的激活可能有助于发病机理。 ATF6途径在神经退行性中的潜在神经保护作用已特别补充难以捉摸。通过增加ER伴侣的产生和增加的降解来增强蛋白质折叠我们提供了错误折叠的蛋白质。与突触脊柱密度相关的认知和行为缺陷活跃的ATF6形式抑制了AD鼠模型中淀粉样蛋白纤维的积累提供有力的证据表明ATF6激活可能在突触活动和认知中具有生理作用行为和急性ATF6激活可以赋予您与AD相关的蛋白毒性的神经保护作用支撑研究，我们的努力将集中于ATF6对神经元的ElucididatiDatiDatil神经孕妇的作用并在神经元和小胶质细胞中区分了ATF6的潜在作用。 ATF6在减弱Aβ斑块形成时，我们将表征特别令人震惊的蛋白质 AD中的蛋白质功能障碍。人类嗜性瘤患者的神经元功能，并确定ATF6的药理学是否激活在AD中具有保护性。并洞悉通过增强UPR功能的潜在策略来逆转损害损害。