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Contribution of BIN1 and Synj1 to endosomal pathogenesis Alzheimer's Disease and Down Syndrome

BIN1 和 Synj1 对阿尔茨海默病和唐氏综合症内体发病机制的贡献

基本信息

批准号：
9904807
负责人：
Laura Beth Johnson McIntire
金额：
$ 40.5万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2019-06-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904807
关键词：
Affect Age Age of Onset Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid beta-Protein Amyloid beta-Protein Precursor Attention BIN1 gene Behavioral Binding Bioinformatics Brain CRISPR/Cas technology Cell model Characteristics Chromosomes, Human, Pair 21 Clathrin Clathrin Adaptors Clinical Trials Complex Data Databases Development Diploidy Disease Disease model Down Syndrome Electrophysiology (science)Endocytosis Endosomes Enzymes Functional disorder Future Gene Expression Gene Fusion Genes Genetic Genetic Polymorphism Human Impaired cognition Individual Kinetics Knock-out Late Onset Alzheimer Disease Lead Lipids Maintenance Mediating Morphology Neighborhoods Nerve Degeneration Neuroglia Neuronal Differentiation Neurons Odds Ratio Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphotransferases Plasma Play Population Production Prosencephalon Protein Family Proteins Reporting Risk Role Signal Transduction Single Nucleotide Polymorphism Synapses Testing Trisomy Validation Vertebral column Viral Work amphiphysin amyloid precursor protein processing cellular targeting disease phenotype fusion gene genetic variant genome wide association study global health high risk improved induced pluripotent stem cell knock-down lipid metabolism member mouse model novel overexpression prevent prophylactic remediation risk variant small hairpin RNA synaptic function synaptojanin text searching therapeutic development trafficking transcriptome sequencing

项目摘要

Alzheimer's disease is predicted to be one of the highest priority global health risks in coming decades, yet there are currently no effective prophylactic or disease modifying therapies. The primary focus in the field has been to target reduction of the synaptotoxic amyloid β-peptide (Aβ) however, recent late-stage clinical trials have proven disappointing. Therefore, new strategies and cellular targets are required. Recent work has found that genetic variants of genes involved in endocytosis such as Bridging Integrator 1 (BIN1 or amphiphysin 2/AMPH2) and phosphatidylinositol-binding clathrin assembly protein (PICALM) correlate with AD risk. Using bioinformatics analysis of STRING Consortium, gene neighborhood, gene fusions, gene co-occurrence, co- expression, experimental data, databases, text mining and protein homology indicate BIN1 is predicted to interact functionally with PICALM and critically, Synaptojanin1 (Synj1). Synj1 is a lipid phosphatase enriched in brain which dephosphorylates the critical signaling lipid phosphatidylinositol-4,5-bisphosphate [P(4,5)P2]. Phosphoinositides, known to be critical for neuronal function, have been shown by our group and others to be altered in AD affected patient brain as well as in mouse models. Synj1 is central to PI(4,5)P2 maintenance at the synapse and we have shown that loss of one copy of Synj1 has been shown to abrogate Aβ-induced synaptic dysfunction. AD and DS show similar pathologies in which APP processing and Aβ is central. DS individuals are trisomic for APP and Synj1, and Synj1 regulatory kinase DYRK1A and are at high-risk for developing AD. Synj1 has been shown to modify endosomal dysfunction in DS mouse models. Current studies have determined that iPSC derived neurons from DS individuals share similar pathogenic hallmarks of AD including increased Aβ42 production and decreased Aβ40:Aβ42 ratio. However, neuronal differentiation displayed normal neuronal conversion kinetics though one study observed exaggerated glia production, a phenotype associated with DS. Therefore, we hypothesize that Synj1 may be central to modifying synaptic and endosomal pathologies in AD and DS. We will test the hypothesis that aberrant Synj1 expression and function in neuronal phenotypes can recapitulate endosomal dysfunction in human induced pluripotent stem cell (iPSC) derived neurons. iPSC from sporadic AD and DS will be differentiated into forebrain neurons. Phenotypes shown to be mediated by Synj1 will be recapitulated in functional human neurons including endosome morphology and function, spine morphology, lipid dysregulation and functional complex formation with BIN1, PICALM, and Dyrk1a. CRISPR/Cas9 will be used to knock-out Synj1 alleles in AD and DS trisomic lines to determine necessity of Synj1 for aberrant phenotypes. Further, it is highly likely that novel cellular targets will emerge from corresponding lipidomic and RNAseq studies of functional iPSC derived neurons. We will also develop critical human neuronal cell models amenable to future therapeutic development.

阿尔茨海默病预计将是未来几十年全球最重要的健康风险之一