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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.

项目总结