SIL1 deficiency causes degenerative changes of peripheral nerves and neuromuscular junctions in fish, mice and human
SIL1 deficiency causes degenerative changes of peripheral nerves and neuromuscular junctions in fish, mice and human
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DOI：
10.1016/j.nbd.2018.11.019
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发表时间：
2019-04
影响因子：
6.1
通讯作者：
Vietxuan Phan;D. Cox;S. Cipriani;S. Spendiff;S. Buchkremer;E. O’Connor;R. Horvath;H. Goebel;D. Hathazi;H. Lochmüller;Tatjana Straka;R. Rudolf;J. Weis;A. Roos
中科院分区：
文献类型：
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作者：
Vietxuan Phan;D. Cox;S. Cipriani;S. Spendiff;S. Buchkremer;E. O’Connor;R. Horvath;H. Goebel;D. Hathazi;H. Lochmüller;Tatjana Straka;R. Rudolf;J. Weis;A. Roos
背景Marinesco-Sjögren 综合征 (MSS) 是一种罕见的神经肌肉疾病，由 SIL1 基因隐性突变引起，导致功能性 SIL1 蛋白缺失，SIL1 蛋白是主要 ER 伴侣 BiP 的辅助伴侣。由于 BiP 对于正确的蛋白质加工至关重要，SIL1 的丢失会导致畸形蛋白质的积累。这种积累可能会损害和破坏脆弱组织中的细胞，导致先天性白内障、小脑共济失调、空泡肌病和其他 MSS 表型。 MSS 中的周围神经系统 (PNS) 是否受到影响尚未得到最终证实。 方法为了研究 MSS 中的 PNS 脆弱性，通过透射电子显微镜和免疫荧光研究以及转录本研究和无偏蛋白质组学分析，对来自 MSS 患者和 SIL1 缺陷小鼠（晕眩）的肌内神经纤维以及这些小鼠的坐骨神经和神经肌肉接头 (NMJ) 进行了研究。此外，通过免疫荧光研究在为此目的而生成的 MSS 斑马鱼模型中分析了 PNS 和 NMJ 的完整性。结果电子显微镜显示形态学变化表明远端轴突和雪旺细胞中的自噬和线粒体维护受损。此外，在 woozymice 小鼠中检测到 NMJ 形态以及编码对 NMJ 功能重要的蛋白质的转录本的变化。这些发现与 SIL1 缺陷斑马鱼胚胎中 NMJ 的严重异常结构一致。对 woozy 小鼠坐骨神经样本的蛋白质组分析显示，与神经元维持有关的蛋白质水平发生了变化，表明补偿机制的激活。结论综上所述，我们的综合数据扩大了受 SIL1 缺失影响的组织范围，并表明神经肌肉传递受损可能是 MSS 病理生理学的一部分。
BackgroundMarinesco-Sjögren Syndrome (MSS) is a rare neuromuscular condition caused by recessive mutations in theSIL1gene resulting in the absence of functional SIL1 protein, a co-chaperone for the major ER chaperone, BiP. As BiP is decisive for proper protein processing, loss of SIL1 results in the accumulation of misshaped proteins. This accumulation likely damages and destroys cells in vulnerable tissues, leading to congenital cataracts, cerebellar ataxia, vacuolar myopathy and other MSS phenotypes. Whether the peripheral nervous system (PNS) is affected in MSS has not been conclusively shown.MethodsTo study PNS vulnerability in MSS, intramuscular nerves fibres from MSS patients and from SIL1-deficient mice (woozy) as well as sciatic nerves and neuromuscular junctions (NMJ) from these mice have been investigatedviatransmission electron microscopic and immunofluorescence studies accompanied by transcript studies and unbiased proteomic profiling. In addition, PNS and NMJ integrity were analyzedviaimmunofluorescence studies in an MSS-zebrafish model which has been generated for that purpose.ResultsElectron microscopy revealed morphological changes indicative of impaired autophagy and mitochondrial maintenance in distal axons and in Schwann cells. Moreover, changes of the morphology of NMJs as well as of transcripts encoding proteins important for NMJ function were detected inwoozymice. These findings were in line with a grossly abnormal structure of NMJs in SIL1-deficient zebrafish embryos. Proteome profiling of sciatic nerve specimens fromwoozymice revealed altered levels of proteins implicated in neuronal maintenance suggesting the activation of compensatory mechanisms.ConclusionTaken together, our combined data expand the spectrum of tissues affected by SIL1-loss and suggest that impaired neuromuscular transmission might be part of MSS pathophysiology.