Division of Clinical Neurobiology, Department of Neurology, Innsbruck Medical University, Austria.
Acta Neuropathol. 2011 Jun;121(6):675-93. doi: 10.1007/s00401-011-0833-z. Epub 2011 May 12.
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.
帕金森病（PD）、路易体痴呆（DLB）和多系统萎缩（MSA）是成人发病的神经退行性疾病，其特征是明显的细胞内α-突触核蛋白聚集（α-突触核蛋白病）。直到最近，神经胶质细胞对α-突触核蛋白病中的神经退行性变的贡献才被大大低估。然而，PD 和 DLB 患者的大脑不仅存在神经元包涵体，如路易体或路易神经突，还存在神经胶质α-突触核蛋白聚集。在 PD 模型中的越来越多的实验证据表明，星形胶质细胞增生和小胶质细胞增生是神经退行性变的重要介导物，在疾病的起始和进展中起着关键作用。在 MSA 中，异常的细胞质内α-突触核蛋白（神经胶质细胞质包涵体，Papp-Lantos 体）聚集会影响少突胶质细胞。来自人类尸检研究和转基因 MSA 模型的一致证据表明，少突胶质细胞功能障碍既触发又加剧神经元变性。本综述总结了星形胶质细胞、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变化。然后，我们对神经胶质细胞在α-突触核蛋白病中的作用进行了批判性分析，包括促进慢性患病的神经胶质微环境的潜在机制，从而导致有害的神经元变化，包括细胞丢失。最后，讨论了针对α-突触核蛋白病中神经胶质病理学的主要治疗策略以及临床试验中疾病修饰的当前困境。
