Miao Zhang, Xinyi Wang, Feiyu Jia, Chenyi Yang, Zixuan Wang, Huihui Liao, Lin Zhang, Xi Xin, Haiyun Wang
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引用次数: 0
Abstract
Aims: Sevoflurane can aggravate the progression of neurodegeneration, although the underlying mechanisms remain incompletely understood. Our previous study identified a link between heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) and sevoflurane-induced neurocognitive impairments. The abnormal hydrogel phase transition of stress granules (SGs) assembled via liquid-liquid phase separation (LLPS) by hnRNPA2/B1 is a crucial element in neurodegeneration. Karyopherin-β2 (Kapβ2) is known to specifically recognize hnRNPA2/B1 and reverses the hydrogel transition of SGs. This study aimed to elucidate the mechanistic role of hnRNPA2/B1-SG phase transition in sevoflurane-induced hippocampal neuronal dysfunction under hypoxic conditions, and to determine whether Kapβ2 can mitigate these effects.
Methods: Using a hypoxic primary rat hippocampal neuron model and Kapβ2 overexpression, we investigated the effects of sevoflurane on hnRNPA2/B1 expression and subcellular distribution, phase separation dynamics, and the liquid-to-solid transition of hnRNPA2/B1-associated SGs. We also assessed neuronal function and cognitive protein expression. Experimental approaches included Western blotting, RT-qPCR, immunofluorescence staining, and fluorescence recovery after photobleaching (FRAP).
Results: In hypoxic hippocampal neurons, sevoflurane altered the nuclear-to-cytoplasmic distribution of hnRNPA2/B1, promoted abnormal LLPS, and facilitated the formation of irreversible solid-phase hnRNPA2/B1-containing SGs. These changes were associated with neuronal dysfunction and reduced expression of cognition-related proteins. Kapβ2 overexpression disrupted these aggregates, restored the dynamic reversibility of hnRNPA2/B1 LLPS, reversed the sevoflurane-induced hydrogel phase transition of hnRNPA2/B1-SGs, and enhanced the expression of cognition-related proteins.
Conclusion: The hydrogel phase transition of hnRNPA2/B1-SG is a key pathological mechanism of sevoflurane-induced hippocampal neuronal injury. Kapβ2 may serve as a potential therapeutic target to counteract sevoflurane-related neurotoxicity.
期刊介绍：
CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
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