Axonal α-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinsons disease
Axonal α-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinsons disease
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DOI：
10.1093/brain/awm302
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发表时间：
2008-03-01
期刊：
影响因子：
14.5
通讯作者：
Takahashi, Hitoshi
中科院分区：
文献类型：
--
作者：
Orimo, Satoshi;Uchihara, Toshiki;Takahashi, Hitoshi
心脏交感神经的变性发生在帕金森病（PD）和路易体痴呆中，并在PD的疾病进展早期开始，导致即使在路易体病（LBD）的早期阶段，心脏对间碘苄胍的摄取也减少。我们以前证明，变性的心交感神经的远端轴突之前的损失，其母神经元在椎旁交感神经节，这表明远端显性变性的心交感神经在PD。由于α-突触核蛋白是这种疾病发病机制中的关键分子之一，我们进一步研究了α-突触核蛋白聚集体如何参与这种远端显性变性。从20例偶发性路易体病（ILBD）患者、10例PD患者、20例多系统萎缩（MSA）患者和10例对照者中获得心脏组织和椎旁交感神经节进行比较。使用针对酪氨酸羟化酶（TH）的抗体作为交感神经的标志物、磷酸化神经丝作为轴突的标志物和磷酸化α-突触核蛋白作为病理沉积物进行免疫组织化学分析。我们发现（i）在ILBD中保留TH-ir轴突的心外膜神经束（即心交感神经的远端轴突）中的α-突触核蛋白聚集体比在该疾病中TH-ir轴突减少和PD中的α-突触核蛋白聚集体丰富得多;（ii）心外膜神经束中的α-突触核蛋白聚集体与TH-ir轴突的消失密切相关;（iii）在具有保留的TH-1 r轴突的ILBD中，α-突触核蛋白聚集体在心外膜神经束中比在椎旁交感神经节中始终更丰富;（iv）ILBD中α-突触核蛋白聚集体的这种远端主导积累被逆转，TH-ir轴突和PD减少，两者都显示较少的这些轴突，但在椎旁交感神经节中更丰富的α-突触核蛋白聚集体，以及（v）基于TH-1 R轴突的保存和在心脏组织或椎旁交感神经节中α-突触核蛋白聚集体的缺乏，MSA与ILBD和PD完全不同。这些研究结果表明，α-突触核蛋白聚集体在心脏交感神经系统的远端轴突中的积累先于椎旁交感神经节中的神经元胞体或神经突的积累，并且预示着PD中心脏交感神经的向心变性，这与MSA中的轻微变化形成鲜明对比。α-突触核蛋白聚集体和心脏交感神经系统的远端显性变性之间的这种时间和动态关系可能代表PD中常见变性过程的病理机制。
Degeneration of the cardiac sympathetic nerve occurs in both Parkinsons disease (PD) and dementia with Lewy bodies and begins early in the disease progression of PD, accounting for reduced cardiac uptake of meta-iodobenzylguanidine even in the early stages of Lewy body disease (LBD). We previously demonstrated that degeneration of the distal axons of the cardiac sympathetic nerve precedes loss of their mother neurons in the paravertebral sympathetic ganglia, suggesting distal dominant degeneration of the cardiac sympathetic nerve in PD. Because alpha-synuclein is one of the key molecules in the pathogenesis of this disease, we further investigated how alpha-synuclein aggregates are involved in this distal-dominant degeneration. Both cardiac tissues and paravertebral sympathetic ganglia were obtained for comparison from 20 patients with incidental Lewy body disease (ILBD), 10 with PD, 20 with multiple system atrophy (MSA) and 10 control subjects. Immunohistochemical analysis was performed using antibodies against tyrosine hydroxylase (TH) as a marker for sympathetic nerves, phosphorylated neurofilament as a marker for axons and phosphorylated alpha-synuclein for pathological deposits. We found that (i) alpha-synuclein aggregates in the epicardial nerve fascicles, namely the distal axons of the cardiac sympathetic nerve, were much more abundant in ILBD with preserved TH-ir axons than in this disease with decreased TH-ir axons and PD; (ii) alpha-synuclein aggregates in the epicardial nerve fascicles were closely related to the disappearance of TH-ir axons; (iii) in ILBD with preserved TH-ir axons, alpha-synuclein aggregates were consistently more abundant in the epicardial nerve fascicles than in the paravertebral sympathetic ganglia; (iv) this distal-dominant accumulation of alpha-synuclein aggregates was reversed in ILBD with decreased TH-ir axons and PD, which both showed fewer of these axons but more abundant alpha-synuclein aggregates in the paravertebral sympathetic ganglia and (v) MSA was completely different from ILBD and PD based on the preservation of TH-ir axons and the scarcity of alpha-synuclein aggregates in either the cardiac tissues or the paravertebral sympathetic ganglia. These findings indicate that accumulation of alpha-synuclein aggregates in the distal axons of the cardiac sympathetic nervous system precedes that of neuronal somata or neurites in the paravertebral sympathetic ganglia and that heralds centripetal degeneration of the cardiac sympathetic nerve in PD, which sharply contrasts with slight changes in MSA. This chronological and dynamic relationship between alpha-synuclein aggregates and distal-dominant degeneration of the cardiac sympathetic nervous system may represent the pathological mechanism underlying a common degenerative process in PD.