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Transcriptome analysis using patient iPSC-derived skeletal myocytes: Bet1L as a new molecule possibly linked to neuromuscular junction degeneration in ALS
Experimental Neurology ( IF 5.3 ) Pub Date : 2021-07-24 , DOI: 10.1016/j.expneurol.2021.113815
Eileen M Lynch 1 , Samantha Robertson 1 , Claire FitzGibbons 1 , Megan Reilly 1 , Colton Switalski 1 , Adam Eckardt 1 , Sin-Ruow Tey 1 , Koji Hayakawa 2 , Masatoshi Suzuki 3
Affiliation  

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease in which patients gradually become paralyzed due to loss of motor function. Many genetically inheritable mutations have been linked to ALS; however, the majority of ALS patients are considered sporadic. Therefore, there is a need for a common therapy that is effective for all ALS patients. Although there is evidence of the disease beginning in the periphery at the neuromuscular junction (NMJ), the specific processes involved in skeletal muscle and at the NMJ are still largely unknown. To study common disease mechanisms in ALS skeletal muscle, we performed RNA sequencing of skeletal myocytes differentiated from induced pluripotent stem cells (iPSCs) derived from familial ALS (with C9ORF72, SOD1, or TARDBP mutations) and sporadic ALS patients. Compared to healthy control lines, the myocytes from all ALS lines showed downregulation of four genes: BET1L, DCX, GPC3, and HNRNPK. We next measured the expression levels of these four genes in hind limb muscle samples from a rat model of familial ALS (SOD1G93A transgenic) and found that only the Bet1L gene, which encodes Bet1 Golgi Vesicular Membrane Trafficking Protein Like, was commonly downregulated. Bet1L protein appeared to be localized to the basal lamina of the NMJ, with decreased expression over time in SOD1G93A transgenic rats. Importantly, the expression levels began to decrease early in the disease process. Our results indicate that loss of Bet1L at the NMJ could be of interest for better understanding ALS disease progression.



中文翻译:

使用患者 iPSC 衍生的骨骼肌细胞进行转录组分析:Bet1L 作为可能与 ALS 中的神经肌肉接头变性有关的新分子

肌萎缩侧索硬化症 (ALS) 是一种致命的神经肌肉疾病,患者由于失去运动功能而逐渐瘫痪。许多遗传上可遗传的突变与 ALS 相关。然而,大多数 ALS 患者被认为是散发性的。因此,需要一种对所有ALS患者都有效的通用疗法。尽管有证据表明该疾病始于神经肌肉接头 (NMJ) 的外周,但涉及骨骼肌和 NMJ 的特定过程仍然很大程度上未知。为了研究 ALS 骨骼肌的常见疾病机制,我们对源自家族性 ALS(具有C9ORF72SOD1TARDBP )的诱导多能干细胞 (iPSC) 分化的骨骼肌细胞进行了 RNA 测序突变)和散发性 ALS 患者。与健康对照品系相比,来自所有 ALS 品系的肌细胞显示出四种基因的下调:BET1LDCXGPC3HNRNPK我们接下来测量了来自家族性 ALS(SOD1 G93A转基因)大鼠模型的后肢肌肉样本中这四种基因的表达水平,发现只有编码 Bet1 高尔基水泡膜运输蛋白样的 Bet1L 基因通常被下调。Bet1L 蛋白似乎定位于 NMJ 的基底层,随着时间的推移在 SOD1 G93A中的表达降低转基因大鼠。重要的是,表达水平在疾病过程的早期就开始下降。我们的结果表明,NMJ 处 Bet1L 的丢失可能有助于更好地了解 ALS 疾病的进展。

更新日期:2021-08-03
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