"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.

项目摘要阿尔茨海默氏病（AD）是最常见的痴呆形式，其特征是错误折叠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原纤维缠结脑。淀粉样斑块包括淀粉样蛋白-B（AB）聚集体的细胞外沉积物，其中Aβ低聚物是被认为是神经元功能的蛋白毒性。大量研究表明，广告相关蛋白毒性触发自适应展开的蛋白质反应（UPR），该反应试图恢复蛋白抑制由于内质网（ER）中错误折叠蛋白的积累而引起的功能障碍。 UPR信号是通过PERK/EIF2A，IRE1/XBP1和ATF6传感器途径介导；这些信号的相对贡献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伴侣水平的升高如BIP/GRP78，人类AD大脑中的GRP94和PDI强烈表明ER应力的慢性激活是证据在人类广告病理学中。此外，以前与XBP1启动子内的双极性疾病有关的多态性地区与中国人口中的AD风险增加有关。尽管已经确定了UPR 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途径在神经变性中的潜在神经保护作用尤其保持难以捉摸。 ATF6充当ER应力传感器和转录因子，促进基因表达通过增加ER伴侣的产生和增加的降解来增强适当的蛋白质折叠错误折叠的蛋白质。我们提供了新的证据，表明ATF6对于突触功能至关重要，因为ATF6 - / - 小鼠显示与突触脊柱密度降低相关的认知和行为缺陷。此外，外源表达在AD的鼠模型中，活性ATF6形式抑制了淀粉样蛋白原纤维的积累。这些结果提供有力的证据表明ATF6激活可能在合成活性和认知中具有身体作用行为和急性ATF6激活可以赋予与AD相关蛋白毒性的神经保护作用。在拟议的研究，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。鉴于 ATF6在减弱Aβ斑块形成时，我们将表征蛋白质，这些蛋白质特别容易受到影响 AD中的蛋白质功能障碍。我们还将表征ATF6突变变体的影响人类嗜性瘤患者的神经元功能，并确定ATF6的药物激活是否是在AD中受到保护。这些结果的总和将使ATF6在神经元/突触函数中隐含新作用，并提供有关通过增强UPR功能来逆转突触障碍的潜在策略的见解。