Role of Prion Protein in Manganese Neurotoxicity

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特征。α -突触核蛋白聚集的渐进性积累与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不清楚。环境中暴露于锰与帕金森症有关，就像人类的神经系统疾病一样。1-突触核蛋白聚集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-突触核蛋白具有一些共同的结构特征，包括多个二价金属结合位点，可以与铜和锰（Mn）等金属结合，以及在纤维化和神经毒性中起作用的GAV共识基序。最近，研究人员观察到锰暴露通过与有助于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处理也上调了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，从而促进疾病进展。因此，最近发现PD中的1-synuclein蛋白聚集与朊病毒病理相似，以及环境锰暴露在帕金森样疾病中的确定作用，导致了一种新的假设，即二价金属锰与1-synuclein和朊病毒蛋白相互作用，促进朊病毒样蛋白聚集的繁殖，从而促进神经退行性过程的进展。一个由一名生物物理学家、一名神经生物学家和一名神经毒理学家组成的跨学科研究小组将利用ViCTER资助机制，从分子水平到系统水平进行详细的研究，以检验这一新的假设。建议要处理的具体目标是：1)在单分子水平上确定暴露于锰是否会增加朊病毒蛋白与1-synuclein之间的亲同性聚集和异性互导，ii)确定暴露于锰与1-synuclein和朊病毒蛋白积累之间的神经病理相互作用，以及iii)确定锰是否与1-synuclein蛋白相互作用以加速朊病毒样蛋白的聚集，从而增加神经元变性。该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。

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.