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Axonal TDP-43 Dysregulation in ALS and Dementia

ALS 和痴呆症中的轴突 TDP-43 失调

基本信息

批准号：
10727012
负责人：
Christopher James Donnelly
金额：
$ 40.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727012
关键词：
Ablation Active Biological Transport Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Automobile Driving Autopsy Axon Axonal Transport Binding Biochemical Brain C9ORF72 Carrier Proteins Cell Nucleus Cells Cytoplasm Cytoplasmic Granules DNA-Binding Proteins Data Data Set Dementia Dendrites Development Disease Distal Evaluation Event Exhibits Exons Functional disorder Future Genes Genetic Genetic Transcription Grant Health Image Impairment Induced pluripotent stem cell derived neurons Injury Kinesin Lasers Length Literature Maintenance Mass Spectrum Analysis Mediating Messenger RNA Microfluidics Morphology Motor Mutation Names Natural regeneration Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Nuclear Protein Nuclear RNA Onset of illness Pathogenicity Pathologic Patients Physiological Play Process Protein Biosynthesis Proteins Proteome Proteomics RNA RNA Processing RNA Splicing RNA Transport RNA-Binding Proteins Ribonucleoproteins Role Spinal Cord Stimulus Tertiary Protein Structure Therapeutic Intervention Tissues Transcript Translating Translations age related anterograde transport axon growth candidate identification extracellular frontotemporal lobar dementia amyotrophic lateral sclerosis functional loss induced pluripotent stem cell injury recovery limbic-predominant age-related TDP-43 encephalopathy mRNA Precursor neuronal cell body neuropathology neurotoxicity prevent protein TDP-43 protein aminoacid sequence protein transport proteostasis response therapeutic development trafficking transcriptome transcriptome sequencing translatome

项目摘要

TDP-43 proteinopathy is a hallmark neuropathology among an array of neurodegenerative disorders, including ALS, FTD, and Alzheimer’s Disease to name a few. Common presentation of TDP-43 proteinopathy includes the mislocalization of TDP-43 from the nucleus to the cytoplasm, disrupting its known function as an RNA-binding protein (RBP). This mislocalization alters global transcriptional dysregulation, such as the increase of cryptic exon expression, as well as effecting local translation of RNAs. Recent studies suggests that TDP-43 is actively transported into the axon, mediated by endolysosomal hitch-hiking on kinesin motors, which is perturbed in neurodegenerative diseases. Moreover, the transport and axonal translation of RNA is important for neuronal function and axon maintenance. Preliminary data from our lab and existing literature, suggests that KIF1A might be a candidate kinesin-motor which facilitates the transport of TDP-43 into the axon. Here, we hypothesize that TDP-43 transports RNA to the axon to facilitate local translation through KIF1A protein, which is perturbed in ALS. The resultant loss of functional TDP- 43 in the axon prevents the localization of key transcripts necessary for de novo protein synthesis and maintenance of the axon. Downstream consequences of this pathogenic event involve the perturbance of the axonal proteotranscriptome, loss of proteostasis, and functional deficits that would otherwise support axon integrity.

TDP-43蛋白质病是一系列神经退行性疾病中的标志性神经病理学。疾病，包括ALS、FTD和阿尔茨海默病等。共同介绍 TDP-43蛋白病包括TDP-43从细胞核到细胞质的错误定位，破坏其作为RNA结合蛋白（RBP）的已知功能。这种错误定位改变了全球转录失调，如隐蔽外显子表达的增加，以及影响 RNA的局部翻译。最近的研究表明，TDP-43被主动转运到轴突，介导的内溶酶体搭便车的驱动蛋白马达，这是扰动，神经退行性疾病此外，RNA的运输和轴突翻译也很重要维持神经元功能和轴突的功能。我们实验室的初步数据和现有文献，提示KIF 1A可能是促进TDP-43转运的候选驱动蛋白-马达进入轴突在这里，我们假设TDP-43将RNA转运到轴突，以促进局部的通过KIF 1A蛋白进行翻译，这在ALS中受到干扰。功能性TDP的丧失- 轴突中的43阻止了从头蛋白质合成所必需的关键转录本的定位和轴突的维护。这一致病事件的下游后果涉及轴突蛋白质转录组的紊乱、蛋白质稳态的丧失和功能缺陷，否则将支持轴突的完整性。