Neurodegeneration Team, Nerve Regeneration Group, IBMC -Instituto de Biologia Molecular e Celular and i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135, Porto, Portugal.
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, 80523, USA.
Cell Death Dis. 2024 Apr 13;15(4):264. doi: 10.1038/s41419-024-06630-9.
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 (PrP) 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.
认知功能障碍和痴呆是路易体痴呆症（LBD）的关键症状。具体来说，α-突触核蛋白（αSyn）在海马体中的积累导致突触功能障碍与 LBD 的认知缺陷有关。在这里，我们研究了 αSyn 对海马神经元的病理影响。我们报告说，αSyn 的过表达或 αSyn 预形成纤维（PFFs）处理都会在培养的海马神经元中和在突触核蛋白病小鼠模型以及 LBD 患者的海马体中触发丝切蛋白-肌动蛋白棒的形成，这是一种破坏突触的物质。在体内，与突触损伤和认知功能障碍同时存在丝切蛋白病理学。αSyn 引发的棒状结构生成涉及细胞朊病毒蛋白（PrP）和趋化因子受体 5（CCR5）的共同作用。重要的是，我们表明，用一种具有临床相关性的肽拮抗剂抑制 CCR5 可以逆转 αSyn 引起的树突棘损伤。总的来说，我们详细描述了 αSyn 破坏海马突触结构的细胞和分子机制，并确定 CCR5 是预防 LBD 中突触损伤和认知功能障碍的新的治疗靶点。
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