title: Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part I, background and methods.
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.
authors.affiliation: Department of Neurobiology and Anatomy, The Neuroscience Program and The ALS Center Winston-Salem, North Carolina.
authors.forename: Sharon
authors.initials: S
authors.lastname: Vinsant
authors.affiliation: Department of Neurobiology and Anatomy, The Neuroscience Program and The ALS Center Winston-Salem, North Carolina.
authors.forename: Carol
authors.initials: C
authors.lastname: Mansfield
authors.affiliation: Department of Neurobiology and Anatomy, The Neuroscience Program and The ALS Center Winston-Salem, North Carolina.
authors.forename: Ramon
authors.initials: R
authors.lastname: Jimenez-Moreno
authors.affiliation: Department of Chemistry, Elon University Elon, North Carolina.
authors.forename: Victoria
authors.initials: V
authors.lastname: Del Gaizo Moore
authors.affiliation: Department of Neurobiology and Anatomy, The Neuroscience Program and The ALS Center Winston-Salem, North Carolina.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yoshikawa
authors.affiliation: Mouse Specifics Boston, Massachusetts.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hampton
authors.affiliation: Department of Neurobiology and Anatomy, The Neuroscience Program and The ALS Center Winston-Salem, North Carolina.
authors.forename: David
authors.initials: D
authors.lastname: Prevette
authors.affiliation: Department of Neurology and the ALS Center, Wake Forest University School of Medicine Winston-Salem, North Carolina.
authors.forename: James
authors.initials: J
authors.lastname: Caress
authors.affiliation: Department of Neurobiology and Anatomy, The Neuroscience Program and The ALS Center Winston-Salem, North Carolina.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Oppenheim
authors.affiliation: Department of Neurobiology and Anatomy, The Neuroscience Program and The ALS Center Winston-Salem, North Carolina.
authors.forename: Carol
authors.initials: C
authors.lastname: Milligan
keywords: Axons; NMJs; cytoplasmic vacuoles; glia; mega-mitochondria; mitochondria; motoneurons; motor function