Institute of Clinical Neurobiology, Kenyongasse 18, 1070 Vienna, Austria.
Acta Neuropathol. 2010 Jun;119(6):657-67. doi: 10.1007/s00401-010-0672-3. Epub 2010 Mar 23.
Multiple systemic atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder of undetermined aetiology characterized by a distinctive oligodendrogliopathy with argyrophilic glial cytoplasmic inclusions (GCIs) and selective neurodegeneration. GCIs or Papp-Lantos inclusions, described more than 20 years ago, are now accepted as the hallmarks for the definite neuropathological diagnosis of MSA and suggested to play a central role in the pathogenesis of this disorder. GCIs are composed of hyperphosphorylated alpha-synuclein (alphaSyn), ubiquitin, LRRK2 (leucin-rich repeat serine/threonine-protein) and many other proteins, suggesting that MSA represents an invariable synucleinopathy of non-neuronal type, a specific form of proteinopathies. The origin of alphaSyn deposition in GCIs is not yet fully understood, but recent findings of dysregulation in the metabolism of myelin basic protein (MBP) and p25alpha, a central nervous system-specific protein, also called TPPP (tubulin polymerization promoting protein), strengthened the working model of MSA as a primary glial disorder and may explain frequent alterations of myelin in MSA. However, it is unknown whether these changes represent an early event or myelin dysregulation occurs further downstream in MSA pathogenesis. The association between polymorphisms at the SNCA gene locus and the risk for developing MSA also points to a primary role of alphaSyn in its pathogenesis, while in a MBP promoter-driven alphaSyn transgenic mouse model gliosis accompanied the neurodegenerative process originating in oligodendrocytes. Because alphaSyn represents a major component in both oligodendroglial and neuronal inclusions in MSA, some authors suggested both a primary oligodendrogliopathy and a neuronal synucleinopathy, but current biomolecular data and animal models support a crucial role of the Papp-Lantos inclusions and of aberrant alphaSyn accumulation as their main constituent, causing oligodendroglial pathology, myelin disruption and, finally, neuronal degeneration in MSA. The relationship between oligodendrocytes involved by Papp-Lantos inclusions and those in degenerating neurons in the course of MSA needs further elucidation.
多系统萎缩（MSA）是一种进行性、成年起病的神经退行性疾病，病因不明，其特征为独特的少突胶质细胞病伴有嗜银性神经胶质细胞胞质包涵体（GCIs）和选择性神经退行性变。GCIs 或 Papp-Lantos 包涵体，在 20 多年前被描述，现在被认为是 MSA 明确神经病理学诊断的标志，并被认为在这种疾病的发病机制中起核心作用。GCIs 由过度磷酸化的α-突触核蛋白（αSyn）、泛素、LRRK2（富含亮氨酸重复丝氨酸/苏氨酸蛋白）和许多其他蛋白质组成，这表明 MSA 代表一种不变的非神经元型突触核蛋白病，是一种特定形式的蛋白病。GCIs 中 αSyn 沉积的起源尚未完全理解，但最近发现髓鞘碱性蛋白（MBP）和 p25α（一种中枢神经系统特异性蛋白，也称为 TPPP（微管聚合促进蛋白））代谢失调，加强了 MSA 作为原发性神经胶质疾病的工作模型，也可能解释 MSA 中髓鞘的频繁改变。然而，尚不清楚这些变化是否代表早期事件，或者 MSA 发病机制中髓鞘失调是否发生在下游。SNCA 基因座多态性与 MSA 发病风险之间的关联也表明 αSyn 在其发病机制中起主要作用，而在 MBP 启动子驱动的αSyn 转基因小鼠模型中，神经胶质增生伴随着起源于少突胶质细胞的神经退行性过程。由于 αSyn 是 MSA 中少突胶质细胞和神经元包涵体的主要成分之一，一些作者提出了原发性少突胶质细胞病和神经元突触核蛋白病，但目前的生物分子数据和动物模型支持 Papp-Lantos 包涵体和异常 αSyn 积累作为其主要成分的关键作用，导致 MSA 中的少突胶质细胞病理学、髓鞘破坏，最终导致神经元变性。在 MSA 过程中，涉及 Papp-Lantos 包涵体的少突胶质细胞与退行性神经元之间的关系需要进一步阐明。
