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The role of CELF2 and its genetic variants in Alzheimer's disease

CELF2及其遗传变异在阿尔茨海默病中的作用

基本信息

批准号：
10551196
负责人：
Lizhen Chen
金额：
$ 45.11万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551196
关键词：
Adult Affect Age Aging Alleles Alternative Splicing 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 Animal Model Animals Autopsy Behavior Behavioral Binding Biochemical Brain Brain region Caenorhabditis elegans Clustered Regularly Interspaced Short Palindromic Repeats Cognition Data Defect Dementia Deposition Disease Elderly Environmental Risk Factor Exons Family Genes Genetic Genetic Polymorphism Genetic Screening Genomics Health High-Throughput Nucleotide Sequencing Hippocampus Homologous Gene Human Human Genetics Immunohistochemistry Immunoprecipitation Impaired cognition Individual Induced pluripotent stem cell derived neurons Introns Knock-in Knock-out Knockout Mice Late Onset Alzheimer Disease Learning Longevity MAPT gene Mammals Measures Memory Messenger RNA Microtubules Minor Modeling Mus Mutation Nerve Degeneration Nervous System Neurodegenerative Disorders Neurons Pathogenesis Pathology Patients Phenotype Play Protein Isoforms Proteins Publishing RNA Splicing RNA Stability RNA-Binding Proteins Regulation Reporting Research Risk Factors Risk Reduction Role Sampling Single Nucleotide Polymorphism Spinal Muscular Atrophy Tauopathies Techniques Testing Tissues Work brain cell calmodulin-dependent protein kinase II cell type comparison control conditional knockout crosslink crosslinking and immunoprecipitation sequencing experience genetic analysis genetic association genetic variant genome wide association study hTau Mice high risk improved induced pluripotent stem cell insight knock-down mRNA Expression member mouse model mutant neurotoxicity new therapeutic target overexpression potential biomarker presenilin-1 presenilin-2 protective effect protein expression risk variant tau Proteins tau expression therapeutic target transcriptome sequencing

项目摘要

Age is the most important risk factor for Alzheimer's disease (AD), but the occurrence of this disease is also affected by environmental factors, individual experience and genetic pre-deposition. Genetic factors are well established to play an important role in risk of AD. CELF2, an RNA binding protein that regulates alternative splicing and RNA stability, has been recently identified as a risk factor associated with AD. Polymorphisms in CELF2 are significantly associated with high-risk alleles of APOE, and the “A” allele of SNP rs2242451 is associated with reduced AD risk. CELF2 is highly expressed in the nervous system, and enhanced neuronal CELF2 expression levels have been found in various neurodegeneration models and human patients. We generated a conditional knockout mouse Celf2 allele. Our preliminary data suggest that deleting Celf2 in adult brain has beneficial effects, including improved learning and memory. We identified mRNA targets of mouse CELF2 (using CLIP-seq; cross-linking immunoprecipitation high-throughput sequencing) and found that CELF2 binds to introns around the alternatively spliced exons of a set of AD- regulated genes, including APP, MAPT (Tau), PSEN1, PSEN2, and BIN1, suggesting a key role of CELF2 in regulating alternative splicing of AD-related genes. Alternative splicing of these AD-related genes is known to regulate AD pathogenesis. For example, alternative splicing of exon 10 of the tau mRNA gives rise to protein isoforms with three (3R) or four (4R) microtubule binding repeats. Imbalances in 4R: 3R ratio alone have been reported sufficient to induce the pathogenesis of AD in a human-Tau mouse model. Taken together with the genetic association between CELF2 SNP and reduced AD risk in humans, we hypothesize that CELF2 expression is up-regulated in AD brains and loss of CELF2 in adult brains is sufficient to rescue AD-related phenotypes. In Specific Aim 1, we will test whether loss of CELF2 can suppress AD-related phenotypes in C. elegans AD models. In Specific Aim 2, we will test whether loss of CELF2 in the adult brain is protective through regulating alternative splicing using AD mouse models. In Specific Aim 3, we will test whether CELF2 expression is increased in AD brains using postmortem human samples and ask if the AD risk-reducing SNP down regulates CELF2 expression or inhibits its function using human iPSC-derived neurons. We have obtained postmortem brain samples and established a strong research team with expertise in genetics, genomics, postmortem AD brains and iPSC. Data from the proposed work will provide important mechanistic insights that go well beyond published human genetic analyses and ultimately yield new therapeutic targets for the treatment of AD.

年龄是阿尔茨海默病（Alzheimer's disease， AD）最重要的危险因素，但这种疾病的发生却越来越少