Mechanisms of Mutant Prion Protein Aggregation Within Endolysosomal Pathways

内溶酶体途径中突变型朊病毒蛋白聚集的机制

基本信息

批准号：
10618881
负责人：
SANDRA E Encalada
金额：
$ 90.82万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618881
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid beta-Protein Architecture Automobile Driving Autopsy Axon Binding Biological Brain Brain Pathology Brain region Cells Characteristics Complex Cytoskeleton Deacetylation Deposition Development Diagnosis Down-Regulation Electron Microscopy Electrons Elements Endocytic Vesicle Endosomes Excision Functional disorder Generations Genetic Goals Golgi Apparatus Health Human Impaired Cytoskeletal Integrity Impairment Investigation Mediating Membrane Microtubules Mission Mitochondria Modeling Molecular Molecular Conformation Multivesicular Body Mus Mutation Nerve Degeneration Neurites Neurodegenerative Disorders Neurologic Neurons Organelles Pathogenesis Pathology Pathway interactions Patients Pharmacological Treatment Poison PrP Prion Diseases Prions Proteins Proteomics Public Health Research Rodent Role Route Site Sorting Structure Testing United States National Institutes of Health Vacuole Vesicle aggregation pathway cofactor design in vivo innovation insight light microscopy mouse model mutant neurofilament neurotoxic novel pharmacologic protein aggregation targeted treatment tau Proteins therapy development trafficking treatment strategy

项目摘要

Ultrastructural studies of human patient brains with prion disease have revealed the accumulation of misfolded PrP within dystrophic neurites inside endolysosomes. Other complex structures co- exist within these dystrophies and are now considered common features of prion pathologies, including autophagic vacuole-like membrane-bound organelles, lysosomal electron-dense bodies, and enlarged endolysosomes. The mechanisms leading to the formation of these structures remain unknown. Our studies have identified an endolysosomal pathway in mammalian neurons that we call axonal rapid endosomal sorting and transport-dependent aggregation (ARESTA), that drives the formation of neurotoxic axonal aggregates of a misfolded mutant prion protein (PrP) inside endo-membrane structures that we call “endoggresomes”. The long-term goal of this proposal is to characterize the endocytic pathways that play a role in the pathophysiology of prion diseases, Alzheimer’s disease, and of Alzheimer’s disease related dementias, that will provide actionable targets for their pharmacological treatment. The objectives of this proposal are (i) to determine the generality of the ARESTA pathway in formation of endoggresomes in axons of neurons expressing various familial PrP mutations, and to characterize the molecular and ultrastructural architecture of neurotoxic endoggresomes; (ii) to determine the mechanisms of mutant PrP endoggresome-mediated axonal impairments; and (iii) to determine how the endolysosomal ARESTA pathway modulates the formation of axonal mutant PrP aggregates in vivo. The central hypotheses are (i) ARESTA drives the formation of endoggresomes in various familial prion diseases by interactions with co-factors within endocytic routes; (ii) mutant PrP endoggresome-induced pathologies act as axonotoxicity hubs that inhibit neuronal function by impairing local axonal cytoskeletal-organelle interactions, and (iii) endolysosomal pathways modulate the formation and pathology of mutant PrP aggregates in vivo. The proposed research is innovative because it provides a conceptual framework for developing models that include novel endolysosomal pathway-mediated mechanisms to explain how intra-axonal aggregates form and impair neuronal function in the prionopathies. The proposed research is significant because it identifies the endocytic pathway and specifically ARESTA and endoggresomes, as anti- aggregation targets for therapies to inhibit aggregate formation and reverse related pathologies. As amyloid-b peptides, tau, and most proteins that misfold in neurodegeneration transit within endocytic routes at some point in their processing routes, our findings are expected to be relevant to Alzheimer’s disease and Alzheimer’s disease related dementias.

人类患者大脑患有prion病的超微结构研究表明积累内溶性内溶性神经内骨质神经病中错误折叠的PRP的错误。其他复杂的结构共同存在于这些营养不良中，现在被认为是病毒病理的常见特征，包括自噬真空胶状膜结合的细胞器，溶酶体电子致密身体和增加的内溶性。导致这些形成的机制结构仍然未知。我们的研究已经确定了哺乳动物的内溶性途径我们称之为轴突快速内体分选和转运依赖性聚集的神经元（Aresta），这驱动了错误折叠突变素的神经毒性轴突聚集体的形成我们称为“内虫”的内膜结构内部蛋白质（PRP）。长期目标该提议的表征是在病理生理中发挥作用的内吞途径病毒疾病，阿尔茨海默氏病和阿尔茨海默氏病有关的痴呆症为其药理治疗提供可行的靶标。该提议的目标是（i）确定轴突中内gre体形成的阿雷斯塔途径的一般性表达各种家庭PRP突变的神经元，并表征分子和神经毒性内og子的超微结构结构；（ii）确定机制突变的PRP内凝介导的轴突损伤；（iii）确定如何内溶性Aresta途径调节轴突突变体PRP聚集体的形成体内。中心假设是（i）Aresta驱动了各种内虫的形成通过与内吞途径中的共同因素相互作用而产生的家族性prion疾病；（ii）突变prp 染色性诱导的病理充当轴突毒性中心，可抑制神经元功能局部轴突细胞骨架 - 轨道相互作用损害（iii）内溶性途径调节体内突变体PRP聚集体的形成和病理。拟议的研究具有创新性，因为它为开发包括新颖的模型提供了一个概念框架内溶性途径介导的机制，以解释轴内聚集体如何形成和临界病中的神经元功能受损。拟议的研究很重要，因为它鉴定内吞途径，特别是Aresta和内粒，是抗用于抑制骨料形成和反向相关病理的疗法的聚集靶标。作为淀粉样蛋白-B肽，TAU和大多数在神经退行性转运中折叠不折叠的蛋白在处理路线的某个时候，内吞途径，我们的发现有望相关阿尔茨海默氏病和阿尔茨海默氏病有关的痴呆症。