中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2017, Vol. 12 ›› Issue (10): 1664-1679.doi: 10.4103/1673-5374.217346

• 原著:退行性病与再生 • 上一篇    下一篇

运动行为分析识别肌萎缩性脊髓侧索硬化症小鼠疾病进展期间早期代偿变化和类型

  

  • 收稿日期:2017-08-28 出版日期:2017-10-15 发布日期:2017-10-15
  • 基金资助:

     NIH基金

Locomotor analysis identifies early compensatory changes during disease progression and subgroup classification in a mouse model of amyotrophic lateral sclerosis

Melissa M. Haulcomb1, 2, Rena M. Meadows1, 2, 3, Whitney M. Miller1, 2, Kathryn P. McMillan1, 2, MeKenzie J. Hilsmeyer1, Xuefu Wang4, Wesley T. Beaulieu4, Stephanie L. Dickinson4, 5, Todd J. Brown1, 2, Virginia M. Sanders6, Kathryn J. Jones1, 2   

  1. 1 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
    2 Research and Development Service, Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
    3 Program in Medical Neurosciences, Indiana University School of Medicine, Indianapolis, IN, USA
    4 Department of Statistics, Indiana University, Bloomington, IN, USA
    5 Department of Epidemiology and Biostatistics, Indiana University, Bloomington, IN, USA
    6 Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA
  • Received:2017-08-28 Online:2017-10-15 Published:2017-10-15
  • Contact: Melissa M. Haulcomb, Ph.D.,mhaulcom@iupui.edu.
  • Supported by:

    This study was supported by a grant from National Institute of Health (NIH), Grant No. NS040433.

PDF

318

摘要：

肌萎缩性脊髓侧索硬化症是一种运动神经元退变疾病，其诊断仍存在一定困难。早期鉴定和提高对症状模式的理解有助于该病的诊断，并为监测疾病进展提供新手段。实验纵向观察了家族性肌萎缩侧索硬化动物模型mSOD1G93A转基因小鼠行为学变化。mSOD1G93A转基因小鼠开始时表现为短暂的后肢代偿性跨阈步态。随着疾病的进展，这种代偿性改变不足以维持行走，出现了更严重的行为缺陷。接下来，实验观察了mSOD1G93A转基因小鼠的存活的固有变异性。应用聚类分析，实验鉴定了行为模式和mSOD1亚群：不同疾病表型和生存率下的快速和缓慢疾病进展组。实验采用的分析方法和行为评估模式为肌萎缩性脊髓侧索硬化症疾病进展的监测和不同疾病严重程度的mSOD1亚组检测提供了方法，从而为进一步研究该病的遗传修饰方法或其他可能加速或延缓疾病的因素提供了机会。

orcid:0000-0001-6464-8402(Melissa M. Haulcomb)

关键词: 神经再生, 肌萎缩性脊髓侧索硬化症, 运动神经元退变性疾病, 运动, SOD1小鼠

Abstract:

Amyotrophic lateral sclerosis is a motoneuron degenerative disease that is challenging to diagnose and presents with considerable variability in survival. Early identification and enhanced understanding of symptomatic patterns could aid in diagnosis and provide an avenue for monitoring disease progression. Use of the mSOD1G93A mouse model provides control of the confounding environmental factors and genetic heterogeneity seen in amyotrophic lateral sclerosis patients, while investigating underlying disease-induced changes. In the present study, we performed a longitudinal behavioral assessment paradigm and identified an early hindlimb symptom, resembling the common gait abnormality foot drop, along with an accompanying forelimb compensatory mechanism in the mSOD1G93A mouse. Following these initial changes, mSOD1 mice displayed a temporary hindlimb compensatory mechanism resembling an exaggerated steppage gait. As the disease progressed, these compensatory mechanisms were not sufficient to sustain fundamental locomotor parameters and more severe deficits appeared. We next applied these initial findings to investigate the inherent variability in B6SJL mSOD1G93A survival. We identified four behavioral variables that, when combined in a cluster analysis, identified two subpopulations with different disease progression rates: a fast progression group and a slow progression group. This behavioral assessment paradigm, with its analytical approaches, provides a method for monitoring disease progression and detecting mSOD1 subgroups with different disease severities. This affords researchers an opportunity to search for genetic modifiers or other factors that likely enhance or slow disease progression. Such factors are possible therapeutic tar ets with the potential to slow disease progression and provide insight into the underlying pathology and disease mechanisms.

Key words: nerve regeneration, amyotrophic lateral sclerosis, motoneuron degenerative disease, locomotor, disease progression, disease variability, SOD1 mouse, neural regeneration