基于先进核分析方法研究帕金森病中的关键金属蛋白及分子机制

Parkinson's disease (PD) is one of the common neurodegenerative diseases among ageing populations. No medication is currently available to prevent or cure PD. PD is believed to be caused by combinatorial effects of genetics, environmental factors and lifestyle. Collectively, monogenic forms of PD only account for less than 8% of total PD cases. Therefore, dissection of non-genetic contributions to PD, such as metal exposure or metal homeostasis, is becoming one of the hot topics in PD research. In this study, we mainly investigate the neurotoxicity of iron and copper by taking advantages of advanced nuclear analytical techniques, including synchrotron radiation. In cell models with different metal status, the relationship between metal toxicity and metal distribution/species will be examined. Meanwhile, two-dimensional gel electrophoresis, when coupled with synchrotron radiation X-ray fluorescence (SRXRF), will be employed to identify metalloproteins on a proteomic scale. The functions of metalloproteins pertinent to the neurotoxicity of metals will be further examined in several PD models. Subsequently, we will focus on identification of metalloproteins which are involved in modulating mitochondrial functions. In particular, the interaction of key metalloproteins with currently known master regulators of mitochondrial biogenesis will be studied to elucidate the implication of mitochondrial dysfunction in PD. In summary, this study will facilitate a better understanding of the contributions of metal toxicity to PD etiology and provide new therapeutic targets for PD. It is envisaged that the employment of advanced nuclear analytical techniques in this study will encourage more applications of these unique methods to addressing key questions in biomedical fields.

帕金森病是一种常见于中老年的神经退行性疾病，目前还没有临床有效的治疗手段。鉴于由单一基因突变引起的病例在总帕金森病例中只占不到8%，近年来环境因素（例如重金属暴露）或生物体内微环境（例如金属的稳态平衡）成为帕金森病研究中新的热点方向。本项目依托项目承担单位在将同步辐射及相关核分析技术应用于生物医学等研究方面的跨学科优势，研究铁、铜等金属的神经细胞毒性。通过建立和优化不同细胞模型，初步探索金属种态和分布与细胞毒性的关系。同时，将X 射线荧光成像结合双向凝胶电泳技术应用于鉴定神经细胞中与金属神经毒性相关的金属蛋白。重点研究参与调节线粒体功能（可能与金属引起的氧化应激相关）的金属蛋白，探索线粒体损伤在帕金森病中可能的作用。本研究结果将有助于阐明铁、铜等金属离子对帕金森病的作用机理，为预防和治疗帕金森病提供新的蛋白靶点。此外，本项目的开展也将有助于促进现代核分析技术在生物医学研究领域的广泛应用。

帕金森病是一种多因素诱导的神经退行性疾病，其具体的发病和病理机制还不清楚。由于目前临床上还没有有效的治疗手段，因此针对帕金森病的相关机制研究显得尤为迫切和重要。本项目依托项目承担单位的大科学装置，结合细胞生物学、化学生物学等多学科交叉的技术和方法，主要探索了二价铁离子和二价铜离子的神经细胞毒性，部分揭示了关键蛋白酶对铁离子或铜离子神经细胞毒性的调控作用和机制。此外，实验数据表明线粒体活性可能与铁离子或铜离子的生物效应紧密相关。在DNA层面，圆二色谱实验表明铁离子和铜离子对G-四链体的稳定性均有显著的作用。这些实验结果将为相关药物研发提供重要的科学依据。尤其是发现铁/铜离子的神经细胞毒性依赖于重要蛋白酶活性对实现个体化诊断和精准医疗具有潜在的重要价值。