Miller Kathryn M, Mercado Natosha M, Sortwell Caryl E
Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
Neuroscience Graduate Program, College of Natural Science, Michigan State University, East Lansing, MI, USA.
NPJ Parkinsons Dis. 2021 Apr 12;7(1):35. doi: 10.1038/s41531-021-00179-6.
The lack of disease-modifying treatments for Parkinson's disease (PD) is in part due to an incomplete understanding of the disease's etiology. Alpha-synuclein (α-syn) has become a point of focus in PD due to its connection to both familial and idiopathic cases-specifically its localization to Lewy bodies (LBs), a pathological hallmark of PD. Within this review, we will present a comprehensive overview of the data linking synuclein-associated Lewy pathology with intracellular dysfunction. We first present the alterations in neuronal proteins and transcriptome associated with LBs in postmortem human PD tissue. We next compare these findings to those associated with LB-like inclusions initiated by in vitro exposure to α-syn preformed fibrils (PFFs) and highlight the profound and relatively unique reduction of brain-derived neurotrophic factor (BDNF) in this model. Finally, we discuss the multitude of ways in which BDNF offers the potential to exert disease-modifying effects on the basal ganglia. What remains unknown is the potential for BDNF to mitigate inclusion-associated dysfunction within the context of synucleinopathy. Collectively, this review reiterates the merit of using the PFF model as a tool to understand the physiological changes associated with LBs, while highlighting the neuroprotective potential of harnessing endogenous BDNF.
帕金森病（PD）缺乏疾病修饰治疗方法，部分原因是对该疾病病因的理解不完整。α-突触核蛋白（α-syn）由于其与家族性和特发性病例的关联，特别是其定位于路易小体（LBs）（PD的一种病理标志），已成为PD研究的一个焦点。在这篇综述中，我们将全面概述将突触核蛋白相关路易病理与细胞内功能障碍联系起来的数据。我们首先介绍在死后人类PD组织中与路易小体相关的神经元蛋白和转录组的变化。接下来，我们将这些发现与体外暴露于α-突触核蛋白预制纤维（PFFs）引发的类路易小体包涵体相关的发现进行比较，并强调该模型中脑源性神经营养因子（BDNF）显著且相对独特的减少。最后，我们讨论BDNF可能对基底神经节发挥疾病修饰作用的多种方式。尚不清楚的是，在突触核蛋白病的背景下，BDNF减轻包涵体相关功能障碍的潜力。总的来说，这篇综述重申了使用PFF模型作为理解与路易小体相关的生理变化的工具的价值，同时强调了利用内源性BDNF的神经保护潜力。
