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TDP-43 acetylation, phase separation, aggregation, and clearance by antibody-mediated degradation

TDP-43 乙酰化、相分离、聚集和抗体介导的降解清除

基本信息

批准号：
10594973
负责人：
GEOFFREY A CHANG
金额：
$ 75.99万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594973
关键词：
ALS patients ATP phosphohydrolase Acetylation Acetyltransferase Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyotrophic Lateral Sclerosis Antibodies Automobile Driving Autopsy Binding Biological Biology Brain Cell model Central Nervous System Complex Cytoplasm Deacetylase Deacetylation Dementia Disease EP300 gene Elderly Engineering Enzymes Excision Exhibits Frontotemporal Dementia Genes Heat-Shock Proteins 70 Hippocampus Histone Deacetylase Human Induced pluripotent stem cell derived neurons Link Liquid substance Mediating Methods Modification Molecular Chaperones Motor Neurons Mutation Names Neurodegenerative Disorders Neurons Nuclear Outcome Pathologic Pathology Patients Periodicity Phase Phase Transition Phosphorylation Property RNA Binding RNA Processing RNA Splicing RNA-Binding Proteins Regulation Reporting Rodent Model Role Spinal Cord Stress Syndrome TDP-43 aggregation Therapeutic Transcription Initiation age related aged efficacy evaluation induced pluripotent stem cell inhibitor insight limbic-predominant age-related TDP-43 encephalopathy mouse model multicatalytic endopeptidase complex mutant nanobodies neuron loss neurotoxicity prevent protein TDP-43 stress granule transcriptome ubiquitin-protein ligase

项目摘要

Cytoplasmic aggregation of TDP-43 has been reported in almost every age-dependent neurodegenerative disease, including in >40% of frontal temporal dementia (FTD), in the hippocampal neurons of Alzheimer's disease (AD) patients, in >90% of ALS, and in ~100% of a recently recognized AD-like dementia in the oldest of the elderly, an AD-like syndrome identified in 2019 and named Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). We have demonstrated that TDP-43 phase separation and aggregation can drive neuronal death independent of RNA binding, stress granule formation, and TDP-43 association with stress granules. We have subsequently identified that acetylation of TDP-43 (which abolishes its RNA binding) drives its separation into liquid spherical annular bodies. These nuclear annuli have liquid annular shells enriched in TDP-43 and liquid centers highly enriched in HSP70 family molecular chaperones. Use of inhibitors of known deacetylases or the proteasome (to mimic the known age-dependent declines in deacetylase and proteasome activities) provokes cytoplasmic TDP-43 aggregation. We propose to determine the biological and pathological role(s) of acetylated TDP-43 and how HSP70 chaperone activity regulates nuclear TDP-43 function and its aggregation in the cytoplasm. We will determine the regulation and biological consequences of acetylated TDP-43 in neurons by identifying the key regulatory enzymes (acetyltranferases and deacetylases) of acetylated TDP-43 and alter TDP-43’s function in RNA splicing and its subcellular localization/aggregation. To understand how HSP70 family molecular chaperones regulates phase transition of TDP-43, we will use Hsc70 (encoded by the HSPA8 gene and the most abundant HSP70 in neurons) and determine how Hsc70 interacts with TDP-43. We will also determine if enhancing the activity of HSP70 (such as HSPA8, which is highly expressed in neurons) ameliorates TDP-43 pathology. We will also develop a potential therapeutic approach for TDP-43 proteinopathies in which rapid proteasome-mediated degradation of aggregated TDP-43 is achieved through an engineered E3 ubiquitin ligase linked to a synthetically evolved nanobody (a single chain antibody derived from an antibody heavy chain) recognizing either acetylated or phosphorylated TDP-43. Outcomes of these efforts will provide key insights for understanding basic aspects of TDP-43 biology and pathobiology in common dementia, and for developing a new concept of therapy that specifically targets TDP- 43 pathology that could potentially benefit aged patients with TDP-43-related dementia.

几乎在每一种年龄依赖性神经退行性疾病中都报道了TDP-43的细胞质聚集