Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination.
Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination.
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DOI：
10.1002/ana.25198
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发表时间：
2018-04
影响因子：
11.2
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Hu B;McCollum M;Ravi V;Arpag S;Moiseev D;Castoro R;Mobley B;Burnette B;Siskind C;Day J;Yawn R;Feely S;Li Y;Yan Q;Shy M;Li J
Charcot-Marie-Tooth 4J型（CMT 4J）是一种罕见的常染色体隐性神经病，由FIG 4中的突变引起，其导致FIG 4蛋白的丢失。本研究探讨CMT 4J节段性脱髓鞘的自然史和机制。在过去的9年中，我们招募并研究了12名CMT 4J患者的队列，其中包括6名新的FIG 4突变。我们使用形态学、电生理学和生物化学方法对这些患者和相关小鼠模型进行了评估。我们发现感觉运动脱髓鞘性多发性神经病在所有患者一致。这种潜在的髓鞘病理学与神经传导研究（NCS）中的传导速度不均匀减慢、传导阻滞和时间离散相关，这些特征与获得性脱髓鞘周围神经疾病中的特征相似。在没有图4的小鼠中也证实了节段性脱髓鞘（图4-/-）。脱髓鞘与神经血屏障薄弱的脊神经根中雪旺氏细胞脱分化和巨噬细胞的增加有关。胞内Ca ~（2+）浓度升高可诱导雪旺细胞去分化。抑制钙离子水平的螯合剂减少脱分化和脱髓鞘的雪旺细胞在体外和体内。有趣的是，小鼠雪旺细胞或神经元中Fig 4的细胞特异性敲除未能引起节段性脱髓鞘。CMT 4J中的髓鞘变化概括了获得性脱髓鞘神经病的特征。这种病理不是雪旺氏细胞自主的。相反，它涉及涉及多种细胞类型的相互作用和异常升高的细胞内Ca 2+的系统过程。在Fig 4 −/−小鼠中注射Ca 2+螯合剂改善了节段性脱髓鞘，从而提供了一种针对脱髓鞘的治疗策略。
Charcot-Marie-Tooth type 4J (CMT4J) is a rare autosomal recessive neuropathy caused by mutations in FIG4 that result in loss of FIG4 protein. This study investigates the natural history and mechanisms of segmental demyelination in CMT4J. Over the past 9 years, we have enrolled and studied a cohort of 12 CMT4J patients, including 6 novel FIG4 mutations. We evaluated these patients and related mouse models using morphological, electrophysiological and biochemical approaches. We found sensory motor demyelinating polyneuropathy consistently in all patients. This underlying myelin pathology was associated with non-uniform slowing of conduction velocities, conduction block, and temporal dispersion on nerve conduction studies (NCS), which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination was also confirmed in mice without Fig4 (Fig4−/−). The demyelination was associated with an increase of Schwann cell dedifferentiation and macrophages in spinal roots where nerve blood barriers are weak. Schwann cell dedifferentiation was induced by the increasing intracellular Ca2+. Suppression of Ca2+ level by a chelator reduced dedifferentiation and demyelination of Schwann cells in vitro and in vivo. Interestingly, cell-specific knockout of Fig4 in mouse Schwann cells or neurons failed to cause segmental demyelination. Myelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca2+. Injection of a Ca2+ chelator in Fig4−/− mice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination.
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影响因子：
4.5
作者：
Hu B;Arpag S;Zhang X;Möbius W;Werner H;Sosinsky G;Ellisman M;Zhang Y;Hamilton A;Chernoff J;Li J
通讯作者：
Li J
影响因子：
16.6
作者：
Dong, Xian-ping;Shen, Dongbiao;Wang, Xiang;Dawson, Taylor;Li, Xinran;Zhang, Qi;Cheng, Xiping;Zhang, Yanling;Weisman, Lois S.;Delling, Markus;Xu, Haoxing
通讯作者：
Xu, Haoxing
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
5.3
作者：
Balino, Pablo;Monferrer, Lidon;Aragon, Carlos M. G.
通讯作者：
Aragon, Carlos M. G.
影响因子：
4.8
作者：
Ikonomov, Ognian C.;Sbrissa, Diego;Shisheva, Assia
通讯作者：
Shisheva, Assia