Characterization of early pathogenesis in the SOD1G93A mouse model of ALS: part I, background and methods

Brain and Behavior

Sharon Vinsant¹  Carol Mansfield¹  Ramon Jimenez-Moreno¹  Victoria Del Gaizo Moore⁴  Masaaki Yoshikawa¹  Thomas G. Hampton²  David Prevette¹  James Caress³  Ronald W. Oppenheim¹ 

[1] Department of Neurobiology and Anatomy, The Neuroscience Program and The ALS Center, Winston-Salem, North Carolina;Mouse Specifics, Boston, Massachusetts;Department of Neurology and the ALS Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina;Department of Chemistry, Elon University, Elon, North Carolina

关键词: Axons;    cytoplasmic vacuoles;    glia;    mega‐mitochondria;    mitochondria;    motoneurons;    motor function;    NMJs;   

DOI  :  10.1002/brb3.143

来源: Wiley

【 摘 要 】

Abstract

Charcot first described amyotrophic lateral sclerosis (ALS) in 1869; however, its causes remain largely unknown and effective, long-term treatment strategies are not available. The first mouse model of ALS was developed after the identification of mutations in the superoxide dismutase 1 (SOD1) gene in 1993, and accordingly most of our knowledge of the etiology and pathogenesis of the disease comes from studies carried out using this animal model. Although numerous preclinical trials have been conducted in the mutant SOD1 mouse models, the results have been disappointing because they did not positively translate to clinical trials. One explanation may be that current understanding of when and where pathogenesis begins is insufficient to accurately guide preclinical trials. Further characterization of these early events may provide insight into disease onset, help in the discovery of presymptomatic diagnostic disease markers, and identify novel therapeutic targets. Here, we describe the rationale, approach, and methods for our extensive analysis of early changes that included an ultrastructural examination of central and peripheral components of the neuromuscular system in the SOD1^G93A mouse and correlated these alterations with early muscle denervation, motor dysfunction, and motoneuron death. We also provide a discussion of published work to review what is known regarding early pathology in the SOD1 mouse model of ALS. The significance of this work is that we have examined early pathology simultaneously in both the spinal cord and peripheral neuromuscular system, and the results are presented in the companion paper (Part II, Results and Discussion). Our results provide evidence as to why a thorough characterization of animal models throughout the life span is critical for a strong foundation to design preclinical trials that may produce meaningful results.

【 授权许可】

CC BY   
© 2013 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

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