Neurodegeneration in multiple sclerosis.

IF 4.6 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL WIREs Mechanisms of Disease Pub Date : 2023-01-01 Epub Date: 2022-08-10 DOI:10.1002/wsbm.1583
Gabrielle M Mey, Kedar R Mahajan, Tara M DeSilva
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Abstract

Axonal loss in multiple sclerosis (MS) is a key component of disease progression and permanent neurologic disability. MS is a heterogeneous demyelinating and neurodegenerative disease of the central nervous system (CNS) with varying presentation, disease courses, and prognosis. Immunomodulatory therapies reduce the frequency and severity of inflammatory demyelinating events that are a hallmark of MS, but there is minimal therapy to treat progressive disease and there is no cure. Data from patients with MS, post-mortem histological analysis, and animal models of demyelinating disease have elucidated patterns of MS pathogenesis and underlying mechanisms of neurodegeneration. MRI and molecular biomarkers have been proposed to identify predictors of neurodegeneration and risk factors for disease progression. Early signs of axonal dysfunction have come to light including impaired mitochondrial trafficking, structural axonal changes, and synaptic alterations. With sustained inflammation as well as impaired remyelination, axons succumb to degeneration contributing to CNS atrophy and worsening of disease. These studies highlight the role of chronic demyelination in the CNS in perpetuating axonal loss, and the difficulty in promoting remyelination and repair amidst persistent inflammatory insult. Regenerative and neuroprotective strategies are essential to overcome this barrier, with early intervention being critical to rescue axonal integrity and function. The clinical and basic research studies discussed in this review have set the stage for identifying key propagators of neurodegeneration in MS, leading the way for neuroprotective therapeutic development. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.

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多发性硬化症的神经变性。
多发性硬化症(MS)的轴突丢失是疾病进展和永久性神经残疾的关键因素。多发性硬化症是中枢神经系统(CNS)的一种异质性脱髓鞘和神经退行性疾病,表现、病程和预后各不相同。免疫调节疗法可降低作为多发性硬化症标志的炎症性脱髓鞘事件的频率和严重程度,但治疗进展性疾病的疗法很少,而且无法治愈。来自多发性硬化症患者、死后组织学分析和脱髓鞘疾病动物模型的数据阐明了多发性硬化症的发病模式和神经变性的潜在机制。核磁共振成像和分子生物标志物已被提出用于确定神经变性的预测因子和疾病进展的风险因素。轴突功能障碍的早期迹象已经显现,包括线粒体贩运受损、轴突结构变化和突触改变。随着炎症的持续以及再髓鞘化受损,轴突会发生退化,导致中枢神经系统萎缩和疾病恶化。这些研究凸显了中枢神经系统慢性脱髓鞘在轴突缺失中的作用,以及在持续的炎症损伤中促进再髓鞘化和修复的困难。再生和神经保护策略对于克服这一障碍至关重要,早期干预对于挽救轴突的完整性和功能至关重要。本综述中讨论的临床和基础研究为确定多发性硬化症神经退行性变的关键传播因素奠定了基础,为神经保护疗法的开发指明了方向。本文归类于免疫系统疾病 > 分子和细胞生理学 神经系统疾病 > 分子和细胞生理学。
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来源期刊
WIREs Mechanisms of Disease
WIREs Mechanisms of Disease MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
11.40
自引率
0.00%
发文量
45
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