SPOP modifies neurodegenerative proteinopathy in Alzheimer’s Disease.

SPOP 可以改善阿尔茨海默病中的神经退行性蛋白病。

基本信息

批准号：
10675938
负责人：
Randall Eck
金额：
$ 4.77万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-16 至 2026-09-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675938
关键词：
Adaptor Signaling Protein Age Age of Onset Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Amyloid beta-Protein Amyotrophic Lateral Sclerosis Automobile Driving Autopsy BRD2 gene Behavioral Binding Biological C9ORF72 CRISPR/Cas technology Caenorhabditis elegans Confocal Microscopy Cullin Proteins Data Dementia Deposition Development Diagnostic Dipeptides Disease Disease model Epigenetic Process Exhibits Frontotemporal Lobar Degenerations Functional disorder Future Genes Genetic Models Genetic Screening Homologous Gene Human Immunohistochemistry Link Liquid substance Longevity Mediating Messenger RNA Modeling Molecular Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Nuclear Nuclear RNA Pathologic Pathology Patients Phase Play Progressive Supranuclear Palsy Proteins Publishing RNA Splicing RNA interference screen Reporter Role Scaffolding Protein Shapes Signal Transduction System Tauopathies Testing Toxic effect Transgenic Animals Transgenic Model Ubiquitin Visualization Work cohort cullin-3 frontal lobe frontotemporal lobar dementia amyotrophic lateral sclerosis genetic approach hormonal signals hyperphosphorylated tau improved in vivo insight locomotor deficit loss of function loss of function mutation multicatalytic endopeptidase complex mutant neuron loss neurotoxicity novel novel therapeutics overexpression prevent protein TDP-43 protein degradation protein function sex tau Proteins tau aggregation tau-1 translational potential ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Aggregated pathological tau protein constitutes one of the diagnostic hallmarks of Alzheimer’s disease (AD) and related disorders (ADRD). The molecular mechanisms by which pathological tau causes dysfunction and degeneration of neurons remain incompletely understood. However, pathological tau driven neuronal dysfunction and neurodegeneration clearly cause dementia. To investigate how pathological tau contributes to neurodegeneration in AD and ADRDs, we established a transgenic model in Caenorhabditis elegans for neurodegeneration driven by human tau aggregation. By employing classical forward genetic approaches, we identified several genes whose loss of function suppresses tauopathy, including spop-1. SPOP (speckle-type POZ protein) is a conserved nuclear adaptor protein for the RING E3 ubiquitin ligase Cullin-3 (CUL3), selecting proteins for degradation in the ubiquitin proteasome system (UPS). After generating a true null allele via CRISPR- cas9, we found that loss of spop-1 dramatically decreases tau accumulation and phosphorylation without altering tau mRNA abundance, rescues lifespan, reduces neurodegeneration, and improves behavioral deficits in tau transgenic animals. In addition to its role in UPS activity, SPOP also undergoes liquid-liquid phase separation (LLPS) localizing to nuclear speckles (NS). Our previously work in C. elegans and AD neurons indicate disruptions to NS function and composition contribute to tau toxicity. Remarkably, loss of spop-1 also rescues C9orf72 dipeptide-repeat toxicity in a C. elegans model of genetic amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Our preliminary results indicate loss of spop-1 suppresses behavioral deficits in C. elegans expressing ALS-linked mutant TDP-43 as well as transgenics co-expressing TDP-43 and tau, which recalculate AD and ADRD relevant interactions. Altogether, our work led us to hypothesize that SPOP functions as a multipurpose regulator of proteinopathy in AD and ADRDs. We hypothesize SPOP-CUL3 UPS activity and SPOP LLPS/NS localization contribute to the underlying mechanisms of tauopathy. To investigate these hypothesizes the specific aims of this project are: SPECIFIC AIMS: (1) Characterize SPOP loss of function in AD/ADRD neurodegenerative proteinopathies, (2) Determine the mechanism by which SPOP loss of function suppresses tauopathy, and (3) Evaluate the translational relevance of SPOP in Alzheimer’s disease. By completing the proposed work, we will uncover new molecular understandings of disease mechanisms including how SPOP protein – as well as nuclear speckles and Cullin-3 – participate in tauopathy and related ADRD co-pathologies. This work will also provide insight into the translational relevance of SPOP in Alzheimer’s disease brains, setting the stage for future study and informing the development of novel therapeutics.

项目摘要综合的病理tau蛋白构成了阿尔茨海默氏病（AD）和相关疾病（ADRD）。病理tau引起功能障碍和的分子机制神经元的变性仍然不完全理解。但是，病理tau驱动的神经元功能障碍神经变性显然会引起痴呆。调查病理学如何贡献 AD和ADRD的神经变性，我们在秀丽隐杆线虫中建立了一个转基因模型神经变性通过人tau聚集。通过采用经典的远期遗传方法，我们确定了几个基因，其功能损失抑制了包括SPOP-1在内的tauopathy。汤匙（斑点型） POZ蛋白）是一种用于环E3泛素连接酶Cullin-3（CUL3）的保守核衔接蛋白，选择在泛素蛋白体系统（UPS）中降解的蛋白质。通过CRISPR生成真正的无效等位基因后 CAS9，我们发现SPOP-1的损失大大降低了Tau的积累和磷酸化而不会改变 tau mRNA丰度，挽救寿命，减少神经变性并改善tau的行为缺陷转基因动物。除了其在UPS活性中的作用外，Spop还经历了液态液相分离（LLP）的位置核斑点（NS）。我们以前在秀丽隐杆线虫和AD神经元中的工作表明对NS功能的中断成分有助于TAU毒性。值得注意的是，SPOP-1的损失还响应C9orf72二肽重复遗传性肌萎缩性侧索硬化症（ALS）和额颞叶的魔法秀丽隐杆线虫模型中的毒性变性（FTLD）。我们的初步结果表明，SPOP-1的损失抑制了秀丽隐杆线虫的行为缺陷表达ALS连接的突变体TDP-43以及transformics共表达TDP-43和TAU，它们重新计算 AD和ADRD相关互动。总的来说，我们的工作使我们假设Spop充当蛋白质病的多功能调节剂广告和adrds。我们假设Spop-Cul3 UPS活性和Spop LLP/NS定位有助于 tauopathy的基本机制。调查这些假设的该项目的具体目的是：具体目的：（1）表征AD/ADRD神经退行性蛋白质中功能的溅射损失，（2）确定功能损失抑制tauopathy的机制，（3）评估 SPOP在阿尔茨海默氏病中的翻译相关性。通过完成拟议的工作，我们将发现对疾病机制的新分子理解包括spop蛋白以及核斑点和库林-3如何参与tauopathy及相关 ADRD的共同病理。这项工作还将洞悉Spop在阿尔茨海默氏症中的转化相关性疾病大脑，为将来的研究奠定了基础，并为新疗法的发展提供了信息。