Glial dysfunction in the pathogenesis of α-synucleinopathies: emerging concepts.
Glial dysfunction in the pathogenesis of α-synucleinopathies: emerging concepts.
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DOI：
10.1007/s00401-011-0833-z
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发表时间：
2011-06
影响因子：
12.7
通讯作者：
Stefanova N
中科院分区：
文献类型：
--
作者：
Fellner L;Jellinger KA;Wenning GK;Stefanova N
帕金森病（PD）、路易体痴呆（DLB）和多系统萎缩（MSA）是以显著的细胞内α-突触核蛋白聚集（α-突触核蛋白病）为特征的成人发作性神经退行性疾病。直到最近，α-突触核蛋白病中神经胶质对神经变性的贡献在很大程度上被低估。然而，PD和DLB患者的脑不仅表现出神经元包涵体，如路易体或路易神经突，而且还表现出神经胶质α-突触核蛋白聚集体。在PD模型中积累的实验证据表明，星形胶质细胞增生和小胶质细胞增生作为神经变性的重要介质，在疾病的发生和进展中起着关键作用。在MSA中，少突胶质细胞受到α-突触核蛋白（胶质细胞胞质内含物，Papp-Lantos小体）异常细胞质积聚的有趣影响。来自人类死后研究和转基因MSA模型的证据表明，少突胶质细胞功能障碍触发并加剧了神经元变性。本文综述了星形胶质细胞、小胶质细胞和少突胶质细胞在健康大脑中的广泛作用，以及与衰老相关的胶质细胞功能的变化。然后，我们对神经胶质在α-突触核蛋白病中的作用进行了批判性分析，包括促进慢性病变神经胶质微环境的假定机制，这可能导致有害的神经元变化，包括细胞丢失。最后，主要的治疗策略，针对神经胶质病理的α-突触核蛋白病，以及目前的缺陷，疾病的修改在临床试验中进行了讨论。
Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are adult onset neurodegenerative disorders characterised by prominent intracellular α-synuclein aggregates (α-synucleinopathies). The glial contribution to neurodegeneration in α-synucleinopathies was largely underestimated until recently. However, brains of PD and DLB patients exhibit not only neuronal inclusions such as Lewy bodies or Lewy neurites but also glial α-synuclein aggregates. Accumulating experimental evidence in PD models suggests that astrogliosis and microgliosis act as important mediators of neurodegeneration playing a pivotal role in both disease initiation and progression. In MSA, oligodendrocytes are intriguingly affected by aberrant cytoplasmic accumulation of α-synuclein (glial cytoplasmic inclusions, Papp-Lantos bodies). Converging evidence from human postmortem studies and transgenic MSA models suggests that oligodendroglial dysfunction both triggers and exacerbates neuronal degeneration. This review summarises the wide range of responsibilities of astroglia, microglia and oligodendroglia in the healthy brain and the changes in glial function associated with ageing. We then provide a critical analysis of the role of glia in α-synucleinopathies including putative mechanisms promoting a chronically diseased glial microenvironment which can lead to detrimental neuronal changes, including cell loss. Finally, major therapeutic strategies targeting glial pathology in α-synucleinopathies as well as current pitfalls for disease-modification in clinical trials are discussed.