Polystyrene nanoplastics trigger pyroptosis in dopaminergic neurons through TSC2/TFEB-mediated disruption of autophagosome-lysosome fusion in Parkinson’s disease

作者：Xiaomei Liang, Yaqi Zeng, Piao Zhang, Baoyu Zhu, Jiezhu Feng, Tongtong Deng, Zhongling Fu, Chengshuai Liu, Chengyu Chen, Yuhu Zhang · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06634-9 · 被引用次数：21 · 研究领域：Autophagy in Disease and Therapy、Inflammasome and immune disorders、Parkinson's Disease Mechanisms and Treatments

BACKGROUND: 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. OBJECTIVES: This study aimed to investigate the impact of PS-NPs on the onset and progression of PD and the underlying mechanisms. METHODS: 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. RESULTS: Bioluminescence imaging and Py-GCMs confirmed that PS-NPs entered the brain w...