An Induced Pluripotent Stem Cell-Derived Neuromuscular Junction Platform for Study of the NGLY1-Congenital Disorder of Deglycosylation,Advanced Therapeutics

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An Induced Pluripotent Stem Cell-Derived Neuromuscular Junction Platform for Study of the NGLY1-Congenital Disorder of Deglycosylation
Advanced Therapeutics ( IF 3.7 ) Pub Date : 2022-07-15 , DOI: 10.1002/adtp.202200009
Trevor Sasserath ₁ , Ashley L Robertson ₁ , Roxana Mendez ₂ , Tristan T Hays ₁ , Ethan Smith ₁ , Helena Cooper ₁ , Nesar Akanda ₂ , John W Rumsey ₁ , Xiufang Guo ₂ , Atena Farkhondeh ₃ , Manisha Pradhan ₃ , Karsten Baumgaertel ₄ , Matthew Might ₅ , Steven Rodems ₄ , Wei Zheng ₃ , James J Hickman _{1,

2}

Affiliation

There are many neurological rare diseases where animal models have proven inadequate or do not currently exist. NGLY1 deficiency, a congenital disorder of deglycosylation, is a rare disease that predominantly affects motor control, especially control of neuromuscular action. In this study, NGLY1-deficient, patient-derived induced pluripotent stem cells (iPSCs) are differentiated into motoneurons (MNs) to identify disease phenotypes analogous to clinical disease pathology with significant deficits apparent in the NGLY1-deficient lines compared to the control. A neuromuscular junction (NMJ) model is developed using patient and wild type MNs to study functional differences between healthy and diseased NMJs. Reduced axon length, increased and shortened axon branches, MN action potential (AP) bursting, and decreased AP firing rate and amplitude are observed in the NGLY1-deficient MNs in monoculture. When transitioned to the NMJ-coculture system, deficits in NMJ number, stability, failure rate, and synchronicity with indirect skeletal muscle stimulation are observed. This project establishes a phenotypic NGLY1 model for investigation of possible therapeutics and investigations into mechanistic deficits in the system.

中文翻译：

用于研究 NGLY1-先天性去糖基化障碍的诱导多能干细胞衍生神经肌肉接头平台

许多神经系统罕见疾病的动物模型已被证明不充分或目前不存在。NGLY1 缺陷是一种先天性去糖基化障碍，是一种主要影响运动控制，尤其是神经肌肉动作控制的罕见疾病。在这项研究中，NGLY1 缺陷、患者来源的诱导多能干细胞 (iPSC) 被分化为运动神经元 (MN)，以识别类似于临床疾病病理学的疾病表型，与对照相比，NGLY1 缺陷细胞系明显存在明显缺陷。使用患者和野生型 MN 开发神经肌肉接头 (NMJ) 模型，以研究健康和患病 NMJ 之间的功能差异。轴突长度减少，轴突分支增加和缩短，MN 动作电位 (AP) 爆发，在单一培养的 NGLY1 缺陷 MN 中观察到 AP 发射率和振幅降低。当过渡到 NMJ 共培养系统时，观察到 NMJ 数量、稳定性、故障率和与间接骨骼肌刺激的同步性方面的缺陷。该项目建立了一个表型 NGLY1 模型，用于研究可能的治疗方法和研究系统中的机械缺陷。

更新日期：2022-07-15

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