Effect of agent and host factors on alpha-synuclein strain pathogenesis

病原体和宿主因素对α-突触核蛋白菌株发病机制的影响

• 批准号: 10754428
• 负责人: Amanda L. Woerman
• 金额: $ 11.5万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754428
• 关键词: Affect; American; Anatomy; Area; Axonal Transport; Binding; Biochemical; Biological; Biological Assay; Biology; Brain; Cell Line; Cell model; Central Nervous System; Chemicals; Chimeric Proteins; Clinical; Disease; Disease Progression; Dynein ATPase; Exhibits; Genetic; Goals; Heterogeneity; Human; In Vitro; Injections; Integration Host Factors; Investigation; Knowledge; Label; Mammalian Cell; Maps; Microtubule Polymerization; Modeling; Molecular; Molecular Conformation; Motor Activity; Movement Disorders; Multiple System Atrophy; Mus; Neural Pathways; Neuroanatomy; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral; Prions; Property; Proteins; Recombinants; Research; Role; Route; Sampling; Shapes; Source; Structure; Sucrose; Symptoms; Synapses; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Mice; Work; alpha synuclein; biophysical properties; clinical heterogeneity; conformer; disease heterogeneity; disease phenotype; experimental study; in vivo; in vivo imaging; innovation; insight; mouse model; nerve transection; nervous system disorder; neuropathology; pre-formed fibril; prion-like; protein misfolding; sciatic nerve; skills; synucleinopathy; tool; transmission process; transport inhibitor

Protein misfolding diseases, or proteinopathies, are a group of invariably fatal neurodegenerative disorders affecting more than 6.8 million Americans. In multiple system atrophy (MSA) and other synucleinopathy patients, the protein α-synuclein (α-syn) misfolds into a self-templating conformation that spreads via a prion- like manner throughout the body, including the central nervous system (CNS). It is hypothesized that the conformation, or strain, that α-syn misfolds into encodes information about the clinical symptoms and neuropathologies a patient will develop. While previous studies focused on the biochemical differences between α-syn strains, the mechanism of how those differences encode distinct biological phenotypes of disease is poorly understood. The long-term goal of our research is to identify the agent and host factors that contribute to the varied clinical presentations observed across synucleinopathies. In this proposal, we will test the hypothesis that strain-specific differences in aggregate transport and neuroanatomical spread contribute to disease pathogenesis. In Aim 1, we will use alexa fluor-labeled α-syn aggregates to investigate the rate and direction of axonal transport in vitro and in vivo. To determine the molecular mechanisms responsible for α-syn transport, we will use chemical and genetic tools to disrupt microtubule polymerization, dynein motor activity, and dynein cargo adaptor binding, and quantify the strain-specific effects on α-syn axonal transport. In Aim 2, we will determine the role of trans-synaptic spread on α-syn strain pathogenesis. To rigorously perform these studies, we will first determine the titer of three different α-syn strains both in vitro and in vivo. We will then use the sciatic nerve injection model, with and without nerve transection, to determine if α-syn neuroinvasion relies exclusively on trans-synaptic spread, of if extraneural pathways contribute to disease pathogenesis when the same titer of each strain is injected. Finally, we will perform a thorough disease pathogenesis study to establish a temporal-spatial map of strain-specific α-syn spread. This work is innovative because it is the first study to investigate how interactions between the host and strain impact disease progression, and to establish between in vitro and in vivo α-syn titers. This work is significant because it is the first to investigate how interactions between host and strain contribute to the mechanisms underlying axonal transport and trans-synaptic spread of disease. Critically, by identifying the cellular and molecular machinery responsible for α-syn propagation, the results of these experiments will lead to new areas of promising investigation.

蛋白质错误折叠疾病或蛋白质病变是一组不可避免的致死性神经退行性疾病