Acta Neuropathol Commun. 2014 Dec 18;2:177. doi: 10.1186/s40478-014-0177-8.
Transthyretin V30M mutation is the most common variant leading to Familial Amyloidotic Polyneuropathy. In this genetic disorder, Transthyretin accumulates preferentially in the extracellular matrix of peripheral and autonomic nervous systems leading to cell death and dysfunction. Thus, knowledge regarding important biological systems for Transthyretin clearance might unravel novel insights into Familial Amyloidotic Polyneuropathy pathophysiology. Herein, our aim was to evaluate the ability of glial cells from peripheral and autonomic nervous systems in Transthyretin uptake and degradation. We assessed the role of glial cells in Familial Amyloidotic Polyneuropathy pathogenesis with real-time polymerase chain reaction, immunohistochemistry, interference RNA and confocal microscopy.
Histological examination revealed that Schwann cells and satellite cells, from an Familial Amyloidotic Polyneuropathy mouse model, internalize and degrade non-fibrillar Transthyretin. Immunohistochemical studies of human nerve biopsies from V30M patients and disease controls showed intracellular Transthyretin immunoreactivity in Schwann cells, corroborating animal data. Additionally, we found Transthyretin expression in colon of this Familial Amyloidotic Polyneuropathy mouse model, probably being synthesized by satellite cells of the myenteric plexus.
Glial cells from the peripheral and autonomic nervous systems are able to internalize Transthyretin. Overall, these findings bring to light the closest relationship between Transthyretin burden and clearance from the nervous system extracellular milieu.
转甲状腺素蛋白 V30M 突变是导致家族性淀粉样多发性神经病的最常见变体。在这种遗传性疾病中，转甲状腺素蛋白优先在周围和自主神经系统的细胞外基质中积累，导致细胞死亡和功能障碍。因此，了解转甲状腺素蛋白清除的重要生物学系统可能会为家族性淀粉样多发性神经病的病理生理学提供新的见解。在此，我们的目的是评估周围和自主神经系统的神经胶质细胞摄取和降解转甲状腺素蛋白的能力。我们通过实时聚合酶链反应、免疫组织化学、干扰 RNA 和共聚焦显微镜评估了神经胶质细胞在家族性淀粉样多发性神经病发病机制中的作用。
组织学检查显示，来自家族性淀粉样多发性神经病小鼠模型的施万细胞和卫星细胞可内化和降解无纤维转甲状腺素蛋白。对 V30M 患者和疾病对照者的人类神经活检的免疫组织化学研究显示，施万细胞中存在转甲状腺素蛋白的细胞内免疫反应性，与动物数据相符。此外，我们还发现这种家族性淀粉样多发性神经病小鼠模型的结肠中有转甲状腺素蛋白表达，可能是由肌间神经丛的卫星细胞合成的。
周围和自主神经系统的神经胶质细胞能够内化转甲状腺素蛋白。总的来说，这些发现揭示了转甲状腺素蛋白负荷与神经系统细胞外环境清除之间最密切的关系。
