Liang Xiaomei, Zeng Yaqi, Zhang Piao, Zhu Baoyu, Feng Jiezhu, Deng Tongtong, Fu Zhongling, Liu Chengshuai, Chen Chengyu, Zhang Yuhu
Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangdong Province, Southern Medical University, Guangzhou, 510080, China.
Guangzhou Key Laboratory of Diagnosis and Treatment for Neurodegenerative Diseases, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangzhou, 510080, China.
J Transl Med. 2025 Jun 5;23(1):631. doi: 10.1186/s12967-025-06634-9.
Parkinson's disease (PD) is a sporadic neurodegenerative disorder with a rising incidence. Environmental toxins are considered the main etiological factor. The increasing use of polystyrene nanoparticles (PS-NPs) has raised concerns about their potential neurotoxic effects in PD.
This study aimed to investigate the impact of PS-NPs on the onset and progression of PD and the underlying mechanisms.
The breach of the blood-brain barrier (BBB) by PS-NPs was assessed using bioluminescence imaging, fluorescence observation, Pyrolysis-Gas Chromatography-Mass Spectrometry (Py-GCMs), transmission electron microscope (TEM), and Evans blue staining. To evaluate the potential promotion of PD by PS-NPs, a 30-day repeated oral administration study was conducted in vivo, during which behavioral changes and alterations in dopaminergic neurons in the substantia nigra were assessed. In vitro cytotoxicity assays were performed following PS-NPs intervention. Molecular biology techniques, including Western blotting and immunofluorescence, were employed to analyze proteins related to pyroptosis and autophagy-lysosomal pathway in both in vivo and in vitro settings. Additionally, proteomic sequencing was utilized to identify the upstream regulator of the autophagy-lysosomal pathway (ALP), and the effects of modulating this target protein on the ALP-pyroptosis pathway were analyzed.
Bioluminescence imaging and Py-GCMs confirmed that PS-NPs entered the brain within 1.5 h. Evans blue staining and TEM showed PS-NPs damaged the BBB. The 30-day oral toxicity revealed that PS-NPs exacerbated behavioral abnormalities and caused dopaminergic neuron loss. Western blotting and immunofluorescence indicated that PS-NPs induced pyroptosis, disrupted autophagic flux, and lowered protein levels involved in autophagosome-lysosome fusion, both in vivo and in vitro. Furthermore, PS-NPs activated the mechanistic target of rapamycin (mTOR) and inhibited the nuclear translocation of Transcription Factor EB (TFEB). Proteomic sequencing identified a deficit of Tuberous Sclerosis Complex (TSC) 2 protein within the mTOR pathway. Immuno-coprecipitation and Coomassie Blue Fast Staining revealed that PS-NPs bound to TSC2 protein, causing disassembly of TSC1-TSC2 complex.
These findings underscore how PS-NPs accelerated PD onset and progression by disrupting autophagosome-lysosome fusion through TSC2-mTOR-TFEB axis, which triggered protein degradation disorders and pyroptosis in dopaminergic neurons. The molecular mechanisms could inform environmental safety regulations concerning nanoplastics and inspire therapeutic strategies for PD.
帕金森病（PD）是一种发病率不断上升的散发性神经退行性疾病。环境毒素被认为是主要病因。聚苯乙烯纳米颗粒（PS-NPs）使用的增加引发了人们对其在帕金森病中潜在神经毒性作用的担忧。
本研究旨在探讨PS-NPs对帕金森病发病和进展的影响及其潜在机制。
使用生物发光成像、荧光观察、热解气相色谱-质谱联用（Py-GCMs）、透射电子显微镜（TEM）和伊文思蓝染色评估PS-NPs对血脑屏障（BBB）的破坏。为评估PS-NPs对帕金森病的潜在促进作用，在体内进行了为期30天的重复口服给药研究，在此期间评估行为变化和黑质中多巴胺能神经元的改变。在PS-NPs干预后进行体外细胞毒性试验。采用蛋白质印迹和免疫荧光等分子生物学技术分析体内和体外与焦亡和自噬-溶酶体途径相关的蛋白质。此外，利用蛋白质组测序鉴定自噬-溶酶体途径（ALP）的上游调节因子，并分析调节该靶蛋白对ALP-焦亡途径的影响。
生物发光成像和Py-GCMs证实PS-NPs在1.5小时内进入大脑。伊文思蓝染色和TEM显示PS-NPs破坏了血脑屏障。为期30天的口服毒性研究表明，PS-NPs加剧了行为异常并导致多巴胺能神经元丢失。蛋白质印迹和免疫荧光表明，PS-NPs在体内和体外均诱导焦亡、破坏自噬流并降低参与自噬体-溶酶体融合的蛋白质水平。此外，PS-NPs激活了雷帕霉素机制性靶标（mTOR）并抑制转录因子EB（TFEB）的核转位。蛋白质组测序确定mTOR途径中结节性硬化复合物（TSC）2蛋白缺乏。免疫共沉淀和考马斯亮蓝快速染色显示PS-NPs与TSC2蛋白结合，导致TSC1-TSC2复合物解体。
这些发现强调了PS-NPs如何通过TSC2-mTOR-TFEB轴破坏自噬体-溶酶体融合，从而加速帕金森病的发病和进展，这引发了多巴胺能神经元中的蛋白质降解紊乱和焦亡。这些分子机制可为有关纳米塑料的环境安全法规提供参考，并为帕金森病的治疗策略提供启示。
