Role of Prion Protein in Manganese Neurotoxicity

描述（由申请人提供）：蛋白质聚集被认为是许多神经退行性疾病（包括帕金森病（PD））的关键病理生理学特征。α-突触核蛋白蛋白聚集的进行性积累与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未得到很好的理解。环境中暴露于锰与人类帕金森氏症样神经系统疾病有关。1-突触核蛋白聚集体通过朊病毒样机制传播的概念在过去两年中出现。朊病毒和1-突触核蛋白共有一些共同的结构特征，包括多个二价金属结合位点，可以结合金属，如铜和锰（Mn）和GAV的共识基序，在fieturization和神经毒性中发挥作用。最近，研究人员观察到锰暴露通过结合到有助于神经毒性的金属结合位点来稳定细胞朊病毒。在研究锰对朊病毒蛋白的影响时，研究人员意外地发现，锰治疗也上调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有助于疾病进展的病理相互作用。因此，最近的发现，1-突触核蛋白蛋白聚集在PD是类似于朊病毒病理和环境锰暴露在帕金森病样条件下的既定作用，导致了一个新的假设，二价金属锰与1-突触核蛋白和朊病毒蛋白相互作用，以促进朊病毒样传播的蛋白质聚集，这有助于神经退行性过程的进展。一个由生物药理学家、神经生物学家和神经毒理学家组成的跨学科研究小组将利用ViCTER资助机制，通过从分子水平到系统水平的详细研究来测试这一新假设。建议中要解决的具体目标是：i）在单分子水平确定暴露于锰是否增加朊病毒蛋白和1-突触核蛋白之间的嗜同性聚集和嗜异性串扰，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，和iii）确定锰是否与1-突触核蛋白相互作用以加速蛋白质的朊病毒样聚集从而增强神经元变性。这个合作研究项目是独一无二的，将为二价金属在PD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。 公共卫生相关性：虽然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氏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和神经毒性传播方面的潜在相互作用。该合作项目的结果将为二价金属在环境相关帕金森病神经退行性过程进展中的作用提供新的见解。

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.