拉弗拉病小鼠模型的神经肌肉接头功能障碍

IF 4 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-14 DOI:10.1242/dmm.050905
Monica Shukla, Deepti Chugh, Subramaniam Ganesh
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引用次数: 0

摘要

拉弗拉病(LD)是一种致命的神经退行性疾病,由编码拉弗林磷酸酶的 EPM2A 基因或编码马林泛素连接酶的 NHLRC1 基因突变引起。LD 的症状包括癫痫发作、共济失调、痴呆和认知能力下降。对 LD 的研究主要集中在大脑的病理生理学方面。少数研究报告了运动症状、肌无力和肌肉萎缩。有趣的是,已知骨骼肌会积聚拉弗拉多糖体。利用拉弗林缺陷小鼠(一种已确立的 LD 模型),我们证明 LD 病理学与神经肌肉接头(NMJ)的结构和功能损伤相关。具体来说,我们发现 NMJ 传输受损,这与 NMJ 相关基因的表达改变、运动终板面积减少、连接破碎以及 NMJ 上完全神经支配连接的丧失相吻合。我们还观察到腰脊髓α运动神经元减少,突触前形态发生显著改变。LD 动物的肌纤维形态紊乱、轻微的 Z 线流变和肌肉萎缩也很明显。总之,我们的研究为了解导致 LD 运动障碍的神经病理性和肌病性改变提供了新的视角。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Neuromuscular junction dysfunction in Lafora disease.

Lafora disease (LD), a fatal neurodegenerative disorder, is caused by mutations in the EPM2A gene encoding laforin phosphatase or NHLRC1 gene encoding malin ubiquitin ligase. LD symptoms include epileptic seizures, ataxia, dementia and cognitive decline. Studies on LD have primarily concentrated on the pathophysiology in the brain. A few studies have reported motor symptoms, muscle weakness and muscle atrophy. Intriguingly, skeletal muscles are known to accumulate Lafora polyglucosan bodies. Using laforin-deficient mice, an established model for LD, we demonstrate that LD pathology correlated with structural and functional impairments in the neuromuscular junction (NMJ). Specifically, we found impairment in NMJ transmission, which coincided with altered expression of NMJ-associated genes and reduced motor endplate area, fragmented junctions and loss of fully innervated junctions at the NMJ. We also observed a reduction in alpha-motor neurons in the lumbar spinal cord, with significant presynaptic morphological alterations. Disorganised myofibrillar patterns, slight z-line streaming and muscle atrophy were also evident in LD animals. In summary, our study offers insight into the neuropathic and myopathic alterations leading to motor deficits in LD.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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