"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：
10132964
负责人：
Timothy Yikai Huang
金额：
$ 97.1万
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/10132964
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 People Chronic Cleaved cell 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 Population 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.

项目概要阿尔茨海默病 (AD) 是最常见的痴呆症，其特征是折叠错误和特定蛋白质的聚集，表现为神经损失、认知能力下降等病理特征以及组织病理学标志，例如淀粉样斑块和神经原纤维缠结的积累大脑中的淀粉样斑块由淀粉样蛋白-b (Ab) 聚集体的细胞外沉积物组成，其中 Aβ 寡聚体是其中的一部分。被认为对神经元功能具有蛋白质毒性。大量研究表明，AD 相关。蛋白质毒性触发适应性未折叠蛋白反应（UPR），试图恢复蛋白质稳态由于内质网 (ER) 信号中错误折叠蛋白的积累而导致功能障碍。通过 PERK/eIF2a、IRE1/XBP1 和 ATF6 传感器通路介导；神经退行性变的武器很复杂，因为它们在介导细胞存活和细胞死亡方面具有双重作用。 PERK/磷酸化 eIF2a、XBP1 mRNA 剪接的升高以及 ER 伴侣水平的增加，例如人类 AD 大脑中的 BiP/GRP78、GRP94 和 PDI 强烈表明 ER 应激的慢性激活是明显的此外，在人类 AD 病理学中，XBP1 启动子内的多态性先前与双相情感障碍有关。尽管普遍定期审议已被证实，但该地区与中国人群 AD 风险增加有关。通路在 AD 等疾病中被激活，目前尚不清楚 UPR 通路是否具有神经保护作用影响，或者它们的激活是否有助于发病机制。 ATF6 通路在神经退行性疾病中的潜在神经保护作用仍然特别明显 ATF6 充当内质网应激传感器和转录因子，促进基因表达。通过增加 ER 伴侣的产生和增加降解来增强正确的蛋白质折叠我们提出了新的证据，证明 ATF6 对于突触功能至关重要，正如 Atf6-/- 小鼠所表现的那样。与突触棘密度降低相关的认知和行为缺陷此外，外源性表达。这些结果表明，活性 ATF6 形式可抑制 AD 小鼠模型中淀粉样原纤维的积累。提供强有力的证据表明 ATF6 激活可能在突触活动和认知方面具有生理作用行为，并且急性 ATF6 激活可以赋予 AD 相关蛋白毒性的神经保护作用。拟议的研究中，我们的努力将集中于阐明 ATF6 对神经元的潜在神经保护作用和突触功能，并区分 ATF6 在神经元和小胶质细胞中的潜在作用。 ATF6 可以减弱 Aβ 斑块形成，我们将表征特别容易受到影响的蛋白质我们还将描述 AD 中发现的 ATF6 突变变异的影响。对人类全色盲患者神经功能的影响，并确定是否药理学激活 ATF6 这些结果的总和意味着 ATF6 在神经元/突触功能中具有新的作用，并深入了解通过增强 UPR 功能逆转突触损伤的潜在策略。