肌动蛋白解聚因子
树突棘
神经科学
海马体
海马结构
生物
突触
细胞生物学
肌动蛋白细胞骨架
生物化学
细胞骨架
细胞
作者
Marina I. Oliveira da Silva,Miguel Santejo,Isaac W. Babcock,Ana Magalhães,Laurie S. Minamide,Seok Joon Won,Erika Castillo,Ellen Gerhardt,Christiane Fahlbusch,Raymond A. Swanson,Tiago F. Outeiro,Ricardo Taipa,Michael R. Ruff,James R. Bamburg,Márcia A. Liz
标识
DOI:10.1038/s41419-024-06630-9
摘要
Cognitive dysfunction and dementia are critical symptoms of Lewy Body dementias (LBD). Specifically, alpha-synuclein (αSyn) accumulation in the hippocampus leading to synaptic dysfunction is linked to cognitive deficits in LBD. Here, we investigated the pathological impact of αSyn on hippocampal neurons. We report that either αSyn overexpression or αSyn pre-formed fibrils (PFFs) treatment triggers the formation of cofilin-actin rods, synapse disruptors, in cultured hippocampal neurons and in the hippocampus of synucleinopathy mouse models and of LBD patients. In vivo, cofilin pathology is present concomitantly with synaptic impairment and cognitive dysfunction. Rods generation prompted by αSyn involves the co-action of the cellular prion protein (PrPC) and the chemokine receptor 5 (CCR5). Importantly, we show that CCR5 inhibition, with a clinically relevant peptide antagonist, reverts dendritic spine impairment promoted by αSyn. Collectively, we detail the cellular and molecular mechanism through which αSyn disrupts hippocampal synaptic structure and we identify CCR5 as a novel therapeutic target to prevent synaptic impairment and cognitive dysfunction in LBD.
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