A Conditioning Lesion Provides Selective Protection in a Rat Model of Amyotrophic Lateral Sclerosis

• Type of Material: Article
• Authors: Colin K. Franz, Emory University; Eric T. Quach, Emory University; Christina A. Krudy, Emory University; Thais Federici, Emory University; Michele A. Kliem, Emory University; Brooke R. Snyder, Emory University; Bethwel Raore, Emory University; Nicholas Boulis, Emory University
• Language: English
• Date: 2009
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: Copyright Franz et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007357
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 4
• Issue: 10
• Start Page: e7357
• End Page: e7357
• Grant/Funding Information: Our experiments were funded by a laboratory start-up grant from Emory University (N.M.B.).
• Research Categories: Biology, Neuroscience; Health Sciences, Medicine and Surgery

Abstract

Background Amyotrophic Lateral Sclerosis (ALS) is neurodegenerative disease characterized by muscle weakness and atrophy due to progressive motoneuron loss. The death of motoneuron is preceded by the failure of neuromuscular junctions (NMJs) and axonal retraction. Thus, to develop an effective ALS therapy you must simultaneously preserve motoneuron somas, motor axons and NMJs. A conditioning lesion has the potential to accomplish this since it has been shown to enhance neuronal survival and recovery from trauma in a variety of contexts. Methodology/Principal Findings To test the effects of a conditioning lesion in a model of familial ALS we administered a tibial nerve crush injury to presymptomatic fALSG93A rats. We examined its effects on motor function, motoneuron somas, motor axons, and NMJs. Our experiments revealed a novel paradigm for the conditioning lesion effect. Specifically we found that the motor functional decline in fALSG93A rats that received a conditioning lesion was delayed and less severe. These improvements in motor function corresponded to greater motoneuron survival, reduced motor axonopathy, and enhanced NMJ maintenance at disease end-stage. Furthermore, the increased NMJ maintenance was selective for muscle compartments innervated by the most resilient (slow) motoneuron subtypes, but was absent in muscle compartments innervated by the most vulnerable (fast fatigable) motoneuron subtypes. Conclusions/Significance These findings support the development of strategies aimed at mimicking the conditioning lesion effect to treat ALS as well as underlined the importance of considering the heterogeneity of motoneuron sub-types when evaluating prospective ALS therapeutics.