Role of Prion Protein in Manganese Neurotoxicity

朊病毒蛋白在锰神经毒性中的作用

• 批准号: 8231115
• 负责人: Anumantha Gounder Kanthasamy
• 金额: $ 37.42万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-09 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231115
• 关键词: Acute; Address; Affect; Alzheimer' s Disease; Binding; Binding Sites; Biological; Brain; Cell Culture Techniques; Cells; Chronic; Coculture Techniques; Consensus; Copper; Cultured Cells; Data; Disease; Disease Progression; Divalent Cations; Environmental Exposure; Exposure to; Funding Mechanisms; Human; Huntington Disease; Infection; Investigation; Knockout Mice; Lead; Length; Link; Manganese; Measures; Metal Binding Site; Metals; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Outcome; Parkinson Disease; Parkinsonian Disorders; Pathology; Play; Prions; Probability; Process; Proteins; Recombinants; Research; Research Personnel; Research Project Grants; Role; Scanning Probe Microscopes; Severity of illness; Site; Spectrum Analysis; System; Testing; Transgenic Mice; alpha synuclein; base; divalent metal; insight; metal chelator; mouse model; mutant; neurochemistry; neurotoxic; neurotoxicity; novel; prion-like; protein aggregate; protein aggregation; recombinant PrP; single molecule; synuclein; synucleinopathy

DESCRIPTION (provided by applicant): Protein aggregation is considered a key pathophysiological feature of many neurodegenerative diseases including Parkinson's disease (PD). The progressive accumulation of alpha-synuclein protein aggregation has been implicated in the progression of disease severity of PD; however, the biological mechanisms underlying the propagation of these diseases are not well understood. Environmental exposure to manganese has been linked to Parkinson's like neurological conditions in humans. The concept that 1-synuclein protein aggregates spread via a prion-like mechanism has emerged in the last two years. Prion and 1-synuclein proteins share some common structural features including multiple divalent metals binding sites that can bind to metals like copper and manganese (Mn) and a GAV consensus motif that plays a role in fibrillization and neurotoxicity. Recently, the investigators observed that manganese exposure stabilizes cellular prion by binding to the metal binding sites contributing to neurotoxicity. While investigating the effect of manganese on prion protein, the investigators unexpectedly found that Mn treatment also upregulates 1-synuclein neuronal cells, suggesting that metal binding to prion and 1-synuclein may promote pathological interactions that contribute to the disease progression. Thus, the recent discovery that 1-synuclein protein aggregation in PD is similar to prion pathology and the established role of environmental manganese exposure in Parkinsonian-like conditions have lead to a novel hypothesis that the divalent metal manganese interacts with 1-synuclein and prion proteins to promote prion-like propagation of protein aggregation, which contributes to the progression of neurodegenerative processes. A transdisciplinary research team comprised of a biophysicist, a neurobiologist, and a neurotoxicologist will use the ViCTER funding mechanism to test this novel hypothesis using detailed investigations from the molecular level to the system level. The specific aims to be addressed in the proposal are: i) to determine at the single molecule level if exposure to manganese increases the homophilic aggregation and heterophilic cross-talk between prion proteins and 1-synuclein, ii) to determine the reciprocal neuropathological interactions between manganese exposure and 1-synuclein and prion protein accumulation, and iii) to determine whether manganese interacts with 1-synuclein protein to accelerate the prion like aggregation of the protein in order to augment neuronal degeneration. This collaborative research project is unique and will provide new insights into the role of divalent metals in the prion-like disease progression of chronic neurodegenerative processes in PD. PUBLIC HEALTH RELEVANCE: Although protein aggregation is considered a hallmark of various neurodegenerative disorders, the effect of environmental neurotoxic metals on protein aggregation processes is not well characterized. This application aims to characterize the effect of manganese on aggregation of a key cellular protein associated with Parkinson's disease, namely 1-synuclein, and to define the potential interaction of 1- synuclein with prion protein with respect to the propagation of protein aggregation and neurotoxicity. The results of this collaborative project will provide new insights into the role of divalent metals in the progression of neurodegenerative processes in environmentally linked Parkinson's disease.

描述（由申请人提供）：蛋白质聚集被认为是包括帕金森病（PD）在内的许多神经退行性疾病的关键病理生理学特征。 α-突触核蛋白聚集体的逐渐积累与 PD 疾病严重程度的进展有关；然而，这些疾病传播的生物学机制尚不清楚。环境中锰的暴露与人类帕金森病等神经系统疾病有关。 1-突触核蛋白聚集体通过类似朊病毒的机制传播的概念是在过去两年出现的。朊病毒和 1-突触核蛋白具有一些共同的结构特征，包括多个可与铜和锰 (Mn) 等金属结合的二价金属结合位点，以及在纤维化和神经毒性中发挥作用的 GAV 共有基序。最近，研究人员观察到，锰暴露通过与导致神经毒性的金属结合位点结合来稳定细胞朊病毒。在研究锰对朊病毒蛋白的影响时，研究人员意外地发现锰治疗还能上调 1-突触核蛋白神经元细胞，这表明金属与朊病毒和 1-突触核蛋白的结合可能促进病理相互作用，从而导致疾病进展。因此，最近发现PD中的1-突触核蛋白聚集与朊病毒病理学相似，并且环境锰暴露在帕金森病样病症中的既定作用导致了一个新的假设，即二价金属锰与1-突触核蛋白和朊病毒蛋白相互作用，促进蛋白质聚集的类似朊病毒的传播，从而促进神经退行性过程的进展。由生物物理学家、神经生物学家和神经毒理学家组成的跨学科研究团队将利用 ViCTER 资助机制，通过从分子水平到系统水平的详细研究来检验这一新假设。该提案要解决的具体目标是：i) 在单分子水平上确定接触锰是否会增加朊病毒蛋白和 1-突触核蛋白之间的同性聚集和异嗜性串扰，ii) 确定锰暴露与 1-突触核蛋白和朊病毒蛋白积累之间的相互神经病理学相互作用，以及 iii) 确定锰是否与 1-突触核蛋白加速蛋白质的朊病毒样聚集，从而加剧神经元变性。这个合作研究项目是独一无二的，将为二价金属在帕金森病慢性神经退行性过程的朊病毒样疾病进展中的作用提供新的见解。 公共健康相关性：尽管蛋白质聚集被认为是各种神经退行性疾病的标志，但环境神经毒性金属对蛋白质聚集过程的影响尚未得到很好的表征。本申请旨在表征锰对与帕金森病相关的关键细胞蛋白（即 1-突触核蛋白）聚集的影响，并确定 1-突触核蛋白与朊病毒蛋白在蛋白聚集传播和神经毒性方面的潜在相互作用。该合作项目的结果将为二价金属在与环境相关的帕金森病的神经退行性过程进展中的作用提供新的见解。