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

基本信息

批准号：
8508781
负责人：
Huaxi Xu
金额：
$ 37.78万
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：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508781
关键词：
Affect Alzheimer&apos 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

项目摘要

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.