中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (2): 266-270.doi: 10.4103/1673-5374.317960

• 综述:退行性病与再生 • 上一篇    下一篇

SYNGR4和PLEKHB1在肌萎缩性侧索硬化模型运动神经元中的失调：对病理生物学的潜在贡献

  

  • 出版日期:2022-02-15 发布日期:2021-10-08

SYNGR4 and PLEKHB1 deregulation in motor neurons of amyotrophic lateral sclerosis models: potential contributions to pathobiology

Rita F. Marques†, Kent E. Duncan*   

  1. Neuronal Translational Control Research Group, Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    †Present address: Institute for Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg, Hamburg, Germany
  • Online:2022-02-15 Published:2021-10-08
  • Contact: Kent E. Duncan, PhD, kent.duncan@zmnh.uni-hamburg.de or kent.duncan5@gmail.com.
  • Supported by:
    Work in the Duncan lab on this topic was supported in part by funding from the Else Kröner Fresenius Stiftung (Co-PI) and the Werner Otto Stiftung (PI) (to KED).

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摘要： Neural Regen Res：运动神经元中SYNGR4和PLEKHB1失调：改变囊泡运输可能导致肌萎缩性侧索硬化症的症状发作
    肌萎缩侧索硬化症是最常见的成年发病的神经再生疾病，影响运动神经元。它的特征是大脑皮层、脑干和脊髓的运动神经元功能逐渐丧失，导致瘫痪和死亡。尽管在动物和细胞模型中定义突变时可导致疾病的基因和建立疾病模型方面取得了重大进展，但仍不清楚为什么在长时间功能正常后突然出现运动症状。最近一项研究将运动神经元特异性RNA-Seq筛选方法应用于TAR-DNA结合蛋白-43驱动的肌萎缩侧索硬化症的标准模型。发现突触素-4和包含B家族成员1的pleckstrin同源结构域在两个不相关的突变TAR-DNA结合蛋白-43驱动的肌萎缩侧索硬化小鼠模型的运动神经元内的蛋白质水平也被解除调控。  
    来自德国汉堡-埃彭多夫大学医学中心的Kent E. Duncan团队认为已经鉴定的两种跨膜蛋白在TAR-DNA结合蛋白-43驱动的肌萎缩侧索硬化症小鼠模型的运动神经元中的水平在疾病的一个关键转变中发生变化：运动症状的年龄依赖性表现。因此，SYNGR4和PLEKHB1有希望作为疾病“驱动者”来调解这一关键转变。然而，它们同样可以是被动的“标记物”，甚至可以发挥积极的“补偿”作用来恢复体内平衡。区分这些替代品对于理解SYNGR4和PLEKHB1如何参与疾病病因以及它们作为治疗靶点的潜力至关重要。假设这些蛋白质确实在驱动或补偿疾病方面发挥积极作用，了解它们在运动神经元中的确切功能以及改变它们的水平如何影响运动神经元健康将是重要的。这可能是具有挑战性的，因为成人运动神经元的体内功能研究是有限的，目前尚不清楚有多少相关的运动神经元细胞生物学改变可以在培养模型中正确地重现。 
文章在《中国神经再生研究（英文版）》杂志2022年2 月 2 期发表。

Abstract: Amyotrophic lateral sclerosis is the most common adult-onset neurodegenerative disease affecting motor neurons. Its defining feature is progressive loss of motor neuron function in the cortex, brainstem, and spinal cord, leading to paralysis and death. Despite major advances in identifying genes that can cause disease when mutated and model the disease in animals and cellular models, it still remains unclear why motor symptoms suddenly appear after a long pre-symptomatic phase of apparently normal function. One hypothesis is that age-related deregulation of specific proteins within key cell types, especially motor neurons themselves, initiates disease symptom appearance and may also drive progressive degeneration. Genome-wide in vivo cell-type-specific screening tools are enabling identification of candidates for such proteins. In this minireview, we first briefly discuss the methodology used in a recent study that applied a motor neuron-specific RNA-Seq screening approach to a standard model of TAR DNA-binding protein-43 (TDP-43)-driven amyotrophic lateral sclerosis. A key finding of this study is that synaptogyrin-4 and pleckstrin homology domain-containing family B member 1 are also deregulated at the protein level within motor neurons of two unrelated mouse models of mutant TDP-43 driven amyotrophic lateral sclerosis. Guided by what is known about molecular and cellular functions of these proteins and their orthologs, we outline here specific hypotheses for how changes in their levels might potentially alter cellular physiology of motor neurons and detrimentally affect motor neuron function. Where possible, we also discuss how this information could potentially be used in a translational context to develop new therapeutic strategies for this currently incurable, devastating disease.  

Key words: amyotrophic lateral sclerosis, glucagon-like peptide-1 receptor, motor neuron disease, mouse model, neurodegeneration, phosphatidylserine, pleckstrin homology domain, synaptogyrin, TAR DNA-binding protein-43, vesicle transport