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.

缺乏针对帕金森氏病（PD）的疾病缓解疗法的部分原因是对疾病病因的不完全了解。由于α-突触核蛋白（α-synynin）与家族性和特发性病例都有联系，特别是其定位于路易体（LB），这是PD的病理学特征，因此α-突触核蛋白已成为PD的关注焦点。在这篇综述中，我们将介绍将突触核蛋白相关的路易病理与细胞内功能障碍联系起来的数据的全面概述。我们首先介绍与死后人类PD组织中的LBs相关的神经元蛋白和转录组的变化。接下来，我们将这些发现与通过体外暴露于α-syn预先形成的原纤维（PFF）引发的LB样内含物相关的发现进行比较，并突出此模型中脑源性神经营养因子（BDNF）的深度和相对独特的减少。最后，我们讨论了BDNF提供多种可能对基底神经节施加疾病缓解作用的方法。在突触核蛋白病的背景下，BDNF减轻与包涵体相关的功能障碍的潜力仍然未知。总体而言，本次审查重申了使用PFF模型作为了解LB相关生理变化的工具的优点，同时强调了利用内源性BDNF的神经保护潜力。我们讨论了BDNF提供多种可能对基底神经节施加疾病改良作用的方法。在突触核蛋白病的背景下，BDNF减轻与包涵体相关的功能障碍的潜力仍然未知。总体而言，本次审查重申了使用PFF模型作为了解LB相关生理变化的工具的优点，同时强调了利用内源性BDNF的神经保护潜力。我们讨论了BDNF提供多种可能对基底神经节施加疾病改良作用的方法。在突触核蛋白病的背景下，BDNF减轻与包涵体相关的功能障碍的潜力仍然未知。总体而言，本次审查重申了使用PFF模型作为了解LB相关生理变化的工具的优点，同时强调了利用内源性BDNF的神经保护潜力。