半乳糖治疗可恢复谷氨酰胺-果糖-6-磷酸转氨酶1 (Gfpt1)缺陷小鼠的神经肌肉接点传递。

IF 3.2 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Stephen Henry Holland, Ricardo Carmona-Martinez, Daniel O'Neil, Kelly Ho, Kaela O'Connor, Yoshiteru Azuma, Andreas Roos, Sally Spendiff, Hanns Lochmüller
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引用次数: 0

摘要

先天性肌无力综合征(CMS)是由参与神经肌肉连接(NMJ)发育、维持和神经传递的蛋白质突变引起的。迄今为止,超过35个基因的突变与CMS的发展有关。谷氨酰胺果糖-6-磷酸转氨酶1 (GFPT1/ GFPT1)作为己糖胺生物合成途径(HBP)的限速酶,产生蛋白质糖基化所必需的副产物(UDP-GlcNAc)。gfpt1缺陷模型的蛋白糖基化受损,影响NMJ的关键蛋白。Leloir途径是一种半乳糖代谢途径,其最终产物是UDP-GalNAc。酶UDP-GalNAc Epimerase (GALE)也可以将过量的UDP-GalNAc转化为UDP-GlcNAc,这是HBP的副产物。我们假设,在gfpt1缺陷模型中,在体外和体内用半乳糖治疗可以挽救受损的蛋白o - glcn酰化,并逆转关键nmj相关蛋白的糖基化状态。研究表明,半乳糖处理在体外激活了gfpt1缺陷C2C12成肌细胞的Leloir通路,并挽救了蛋白o - glcn酰化。此外,我们在骨骼肌特异性Gfpt1敲除小鼠模型中证明了半乳糖治疗可挽救神经肌肉缺陷,改善肌肉疲劳并恢复NMJ形态。最后,我们发现半乳糖处理恢复了骨骼肌中o - glcn酰化蛋白,保留了乙酰胆碱受体(AChRδ) δ亚基的糖基化状态。综上所述,我们建议可以进一步探索半乳糖补充作为GFPT1-CMS患者的治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Galactose treatment rescues neuromuscular junction transmission in glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) deficient mice.

Congenital myasthenic syndromes (CMS) arise from mutations to proteins involved in neuromuscular junction (NMJ) development, maintenance, and neurotransmission. To date, mutations in more than 35 genes have been linked to CMS development. Glutamine fructose-6-phosphate transaminase 1 (GFPT1/Gfpt1) serves as the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), producing the byproduct (UDP-GlcNAc) necessary for protein glycosylation. Gfpt1-deficient models have impaired protein glycosylation, impacting key proteins at the NMJ. The Leloir pathway is a galactose metabolizing pathway which produces UDP-GalNAc as its final product. The enzyme UDP-GalNAc Epimerase (GALE) can also convert excess UDP-GalNAc into UDP-GlcNAc, the byproduct of the HBP. We hypothesized that treatment with galactose both in vitro and in vivo in Gfpt1-deficient models would rescue impaired protein O-GlcNAcylation and reverse the glycosylation status of key NMJ-associated proteins. We show that galactose treatment in vitro activated the Leloir pathway and rescued protein O-GlcNAcylation in Gfpt1-deficient C2C12 myoblasts. In addition, we demonstrated that galactose therapy rescued neuromuscular deficits, improved muscle fatigue and restored NMJ morphology in a skeletal muscle-specific Gfpt1 knockout mouse model. Lastly, we showed that galactose treatment rescued protein O-GlcNAcylation in skeletal muscle, preserving the glycosylation status of the delta (δ) subunit of the acetylcholine receptor (AChRδ). Taken together, we suggest that galactose supplementation can be further explored as a therapy for GFPT1-CMS patients.

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来源期刊
Human molecular genetics
Human molecular genetics 生物-生化与分子生物学
CiteScore
6.90
自引率
2.90%
发文量
294
审稿时长
2-4 weeks
期刊介绍: Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include: the molecular basis of human genetic disease developmental genetics cancer genetics neurogenetics chromosome and genome structure and function therapy of genetic disease stem cells in human genetic disease and therapy, including the application of iPS cells genome-wide association studies mouse and other models of human diseases functional genomics computational genomics In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.
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