Department of Psychiatry, Loma Linda University, Loma Linda, CA, United States.
Department of Psychiatry, Patton State Hospital, San Bernardino, CA, United States.
Front Cell Infect Microbiol. 2022 Mar 24;12:845580. doi: 10.3389/fcimb.2022.845580. eCollection 2022.
A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a "decentralized" information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.
越来越多的流行病学和研究数据表明，神经病毒与大脑加速衰老和神经退行性疾病风险增加有关。许多病毒在衰老细胞中最佳复制，因为衰老细胞提供了一个适宜的微环境，其中细胞质钙持续升高、细胞内铁丰富、I 型干扰素水平低。由于细胞融合是细胞衰老的主要驱动因素，许多病毒已经发展出通过形成合胞体来促进这种表型的能力。细胞融合与通过磷脂酰丝氨酸外化介导的免疫抑制有关，这使病毒能够逃避宿主防御。在宿主中，病毒诱导的免疫功能障碍和过早的细胞衰老可能导致神经退行性疾病。这一概念得到了一些新研究的支持，这些研究发现几种病毒感染性疾病（包括人类免疫缺陷病毒 1、单纯疱疹病毒 1 和 SARS-CoV-2）后存在感染后认知功能障碍。病毒诱导的病理性合胞体可能为概念化神经元细胞周期再进入、非整倍体、体细胞镶嵌、病理性 Tau 的病毒传播以及神经毒性星形胶质细胞和小胶质细胞对有活力的突触和神经元的消除提供了一个统一的框架。在这篇叙述性综述中，我们更仔细地研究了细胞融合和神经退行性疾病发病机制中的小泡融合。我们提出了一个“去中心化”的信息处理模型，将神经退行性变概念化为一种全身性疾病，由细胞骨架病理学引发。我们还讨论了逆转细胞融合的策略，包括 TMEM16F 抑制剂、钙通道阻滞剂、衰老细胞清除剂和微管稳定剂。最后，超越神经退行性变，我们研究了利用融合作为再生医学中治疗策略的潜在益处。
