Roles of an APP-binding pro-apoptotic protein in mediating neuronal cell death

APP 结合促凋亡蛋白在介导神经元细胞死亡中的作用

• 批准号: 8699621
• 负责人: Huaxi Xu
• 金额: $ 39.98万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699621
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Apoptosis; Apoptotic; BCL2 gene; Basic Science; Behavior; Behavioral; Biological Process; Brain; Brain region; C-terminal; Carrier Proteins; Caspase; Cell physiology; Cessation of life; Cleaved cell; Cytoplasm; Data; Disease; Down-Regulation; Event; Family member; Functional disorder; Generations; Genetic Transcription; Glutamates; Knockout Mice; Link; Malignant Neoplasms; Mediating; Membrane Potentials; Memory; Mitochondria; Mitochondrial Matrix; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Peptides; Physiological; Play; Protein Binding; Protein Family; Proteins; Reactive Oxygen Species; Rodent; Role; Sampling; Senile Plaques; Stress; Stroke; Synapses; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; amyloid precursor protein processing; apoptosis inducing factor; caspase-3; caspase-9; combat; cytochrome c; cytotoxic; excitotoxicity; extracellular; fight against; in vivo; mitochondrial membrane; mouse model; neuron apoptosis; neuron loss; neuronal survival; neurotoxic; neurotoxicity; new therapeutic target; novel; overexpression; peptide A; prevent; pro-apoptotic protein; protein metabolism; protein metabolite; response; secretase; tau Proteins

DESCRIPTION (provided by applicant): Apoptosis is an essential cellular process important for many physiological functions. Dysregulation of apoptosis has been found to be involved in multiple diseases including cancers and neurodegenerative diseases. Neurons, after suffering various insults, undergo apoptosis in neurodegenerative diseases. Identification of new proteins mediating apoptosis and elucidation of the underlying mechanisms will be important for developing new strategies to fight against these diseases. An important pathologic feature and the primary cause of Alzheimer's disease (AD) is overproduction/accumulation of ?-amyloid (A?) peptides that form extracellular senile plaques in the brain. A? peptides are derived from ?-amyloid precursor protein (APP) through sequential cleavages by ?-secretase and ?-secretase. Cleavage of APP by ?-secretase also releases the intracellular domain of APP (AICD) which has been suggested to play a role in gene transcription regulation. Moreover, APP, ?-cleaved C-terminal fragment of APP (C99), AICD and smaller fragments (C31 and Jcasp), derived from AICD by caspase cleavage, have been shown to be cytotoxic when overexpressed, suggesting their involvement in apoptosis. In our preliminary studies, we have identified an APP/AICD-interacting protein, appoptosin (also known as SLC25A38), which belongs to the mitochondrial carrier protein (MCP) family. Importantly, we find that appoptosin is a pro-apoptotic protein and its overexpression can induce caspase-dependent apoptosis, for which APP is partially required. In addition, the level of appoptosin is elevated in AD brains and in neurons upon insult treatments, whereas downregulation of appoptosin can protect neurons against neurotoxicity. Therefore, we hypothesize that appoptosin-mediated apoptosis plays an important role in neurotoxicity-induced neurodegenerative diseases such as AD. In this application, we will further study the molecular pathways underlying the apoptosis induced by appoptosin and identify the biological function of appoptosin. We will ascertain whether and how APP and its metabolites affect appoptosin and reciprocally, study whether appoptosin regulates APP processing/A? generation. Furthermore, we will investigate any change in the activity, concentration or localization of appoptosin in the brain samples of AD patients and transgenic mice to establish a direct link between appoptosin and AD. Moreover, we will generate appoptosin (conditional) knockout mice to study its physiological functions. By crossing brain-specific appoptosin knockout mice with an AD mouse model, we will determine whether a deficiency of appoptosin in the brain can ameliorate AD-like pathologies and memory/behavioral deficits in the AD mice. Together, our studies will elucidate the mechanism underlying appoptosin-mediated apoptosis and demonstrate its importance in neuronal death associated with degenerative insults. The results should reveal appoptosin as a new therapeutic target for multiple diseases, such as neurodegenerative diseases and cancers.

描述（由申请人提供）：凋亡是许多生理功能重要的细胞过程。凋亡的失调与包括癌症和神经退行性疾病在内的多种疾病有关。神经元在遭受各种侮辱后会在神经退行性疾病中凋亡。鉴定介导凋亡和阐明基本机制的新蛋白质对于制定对抗这些疾病的新策略至关重要。一个重要的病理性特征和阿尔茨海默氏病（AD）的主要原因是？ - 淀粉样蛋白（A？）肽的过量生产/积累，在大脑中形成细胞外的老年斑块。一个？肽是从？淀粉样蛋白前体蛋白（APP）通过？ - 分泌酶和？分泌酶的顺序切割。通过？分泌酶对APP的切割还释放了APP（AICD）的细胞内结构域，该域被认为在基因转录调控中发挥作用。此外，APP（C99）（C99），AICD和较小片段（C31和JCASP）的APP，APP，由caspase裂解从AICD衍生而来，在过表达时已显示为细胞毒性，这表明它们的参与率是细胞毒性。在我们的初步研究中，我们确定了属于线粒体载体蛋白（MCP）家族的App/AICD相互作用蛋白Appoptosin（也称为SLC25A38）。重要的是，我们发现appoptosin是一种促凋亡蛋白，其过表达可以诱导caspase依赖性凋亡，以部分应用APP。此外，在损伤治疗后，AD脑和神经元中的杂菌素水平升高，而appoptosin的下调可以保护神经元免受神经毒性的影响。因此，我们假设杂多蛋白介导的细胞凋亡在神经毒性诱导的神经退行性疾病（如AD）中起重要作用。在此应用中，我们将进一步研究appoptosin诱导的细胞凋亡的基本途径，并确定appoptosin的生物学功能。我们将确定应用程序及其代谢物如何影响appoptosin并相互影响，研究appoptosin是否调节应用程序处理/A？一代。此外，我们将研究Apoptosin在AD患者和转基因小鼠的大脑样本中的活性，浓度或定位的任何变化，以建立Appoptosin和AD之间的直接联系。此外，我们将生成appoptosin（条件）敲除小鼠以研究其生理功能。通过将大脑特异性的杂菌素基因敲除小鼠与AD鼠标模型跨越，我们将确定大脑中appopoptosin的缺乏是否可以改善AD小鼠中类似AD的病理和记忆/行为缺陷。总之，我们的研究将阐明丘脑介导的细胞凋亡的基本机制，并证明其在与退化性损伤相关的神经元死亡中的重要性。结果应揭示杂菌素是多种疾病的新治疗靶点，例如神经退行性疾病和癌症。