Role of Prion Protein in Manganese Neurotoxicity

描述(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-突触核蛋白聚集的进行性积累与帕金森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。环境中的锰暴露与人类的帕金森氏症神经系统疾病有关。在过去的两年里，1-突触核蛋白聚集体通过类似普里恩的机制传播的概念已经出现。朊病毒和1-突触核蛋白有一些共同的结构特征，包括可以与铜、锰等金属结合的多个二价金属结合部位，以及在纤化和神经毒性中发挥作用的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部位结合来稳定细胞内的普恩。在研究锰对普恩蛋白的影响时，研究人员出人意料地发现，锰处理还上调了1-突触核蛋白神经细胞，这表明金属与普恩蛋白和1-突触核蛋白的结合可能促进了有助于疾病进展的病理相互作用。因此，最近发现1-突触核蛋白在帕金森病中的聚集类似于普恩病毒的病理，以及环境中锰暴露在帕金森病样条件下所起的作用，这导致了一个新的假说，即二价金属锰与1-突触核蛋白和普恩蛋白相互作用，促进蛋白质聚集的普恩样繁殖，从而促进神经退变过程的进展。一个由生物物理学家、神经生物学家和神经毒物学家组成的跨学科研究小组将使用Victer资助机制，通过从分子水平到系统水平的详细调查来验证这一新假说。该提案要解决的具体目标是：i)在单分子水平上确定暴露于锰是否会增加普恩蛋白和1-突触核蛋白之间的亲同性聚集和异嗜性串扰，ii)确定接触锰与1-突触核蛋白和普恩蛋白积累之间的相互神经病理相互作用，以及iii)确定锰是否与1-突触核蛋白相互作用以加速蛋白的类普恩聚集，从而增加神经元的变性。这一合作研究项目是独一无二的，将为二价金属在帕金森病的慢性神经退行性变过程中的普恩病样疾病进展中的作用提供新的见解。 公共卫生相关性：尽管蛋白质聚集被认为是各种神经退行性疾病的标志，但环境中的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。本应用旨在研究锰对与帕金森氏病相关的关键细胞蛋白--1-突触核蛋白聚集的影响，并确定1-突触核蛋白与蛋白在蛋白质聚集和神经毒性方面的潜在相互作用。这一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化过程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.