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

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.

• Publication year

  2009

• Venue

  PLoS ONE

• Publication date

  2009-10-06

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pone.0007357PMID 19806196PMCID 2752158
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Neurotrophic Modulation of Motor Neuron Development

  2009cited by this paper
• Intraspinal cord delivery of IGF-I mediated by adeno-associated virus 2 is neuroprotective in a rat model of familial ALS.

  2009cited by this paper
• The role of neurotrophic factors in nerve regeneration.

  2009cited by this paper
• Preferential motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis

  2008cited by this paper
• A randomized controlled trial of resistance exercise in individuals with ALS

  2007cited by this paper
• Time course of preferential motor unit loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis.

  2007cited by this paper
• Sports and trauma in amyotrophic lateral sclerosis revisited.

  2007cited by this paper
• Heterogeneity in motoneuron disease.

  2007cited by this paper
• Synaptic dysfunction in disease and following injury in the developing and adult nervous system: caveats in the choice of therapeutic intervention.

  2007cited by this paper
• The Motoneurone and its Muscle Fibres

  2007cited by this paper
• The motoneurone and its muscle fibres

  2007cited by this paper
• Gene‐based treatment of motor neuron diseases

  2006cited by this paper
• Disease progression of human SOD1 (G93A) transgenic ALS model rats

  2006cited by this paper
• Analysis of factors that modify susceptibility and rate of progression in amyotrophic lateral sclerosis (ALS)

  2006cited by this paper
• Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF

  2006influential reference
• Motoneuron degeneration after facial nerve avulsion is exacerbated in presymptomatic transgenic rats expressing human mutant Cu/Zn superoxide dismutase

  2005influential reference
• The effect of peripheral nerve injury on disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.

  2005influential reference
• Synergy of insulin‐like growth factor‐1 and exercise in amyotrophic lateral sclerosis

  2005cited by this paper
• Physical activity and the association with sporadic ALS

  2005cited by this paper
• Properties of slow- and fast-twitch muscle fibres in a mouse model of amyotrophic lateral sclerosis.

  2005cited by this paper
• Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players.

  2005cited by this paper
• Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man.

  2004cited by this paper
• Sexual differences in onset of disease and response to exercise in a transgenic model of ALS.

  2003cited by this paper
• Effect of NT‐4 and BDNF delivery to damaged sciatic nerves on phenotypic recovery of fast and slow muscles fibres

  2003cited by this paper
• Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis

  2003cited by this paper
• Differential tyrosine kinase C mRNA distribution in extensor digitorum longus and soleus motoneurons in adult rats: effect of axotomy and neurotrophin-3 treatment.

  2002cited by this paper
• Altered reaction of facial motoneurons to axonal damage in the presymptomatic phase of a murine model of familial amyotrophic lateral sclerosis.

  2002influential reference
• Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS)

  2002cited by this paper
• Premorbid weight, body mass, and varsity athletics in ALS

  2002cited by this paper
• A possible role for BDNF, NT-4 and TrkB in the spinal cord and muscle of rat subjected to mechanical overload, bupivacaine injection and axotomy.

  2001cited by this paper
• Motoneuron cell death and neurotrophic factors: Basic models for development of new therapeutic strategies in ALS

  2001cited by this paper
• The value of muscle exercise in patients with amyotrophic lateral sclerosis.

  2001cited by this paper
• Early and Selective Loss of Neuromuscular Synapse Subtypes with Low Sprouting Competence in Motoneuron Diseases

  2000cited by this paper
• Differential effects of NT‐3 on reinnervation of the fast extensor digitorum longus (EDL) and the slow soleus muscle of rat

  2000cited by this paper
• Reduction of axonal caliber does not alleviate motor neuron disease caused by mutant superoxide dismutase 1.

  2000cited by this paper
• Peripheral axotomy slows motoneuron degeneration in a transgenic mouse line expressing mutant SOD1 G93A

  1999influential reference
• Can amyotrophic lateral sclerosis patients with respiratory insufficiency exercise?

  1999cited by this paper
• Risk of amyotrophic lateral sclerosis and history of physical activity: a population-based case-control study.

  1998cited by this paper
• Massive Mitochondrial Degeneration in Motor Neurons Triggers the Onset of Amyotrophic Lateral Sclerosis in Mice Expressing a Mutant SOD1

  1998cited by this paper
• Neurotrophin-3–enhanced Nerve Regeneration Selectively Improves Recovery of Muscle Fibers Expressing Myosin Heavy Chains 2b

  1997cited by this paper
• Intrinsic versus extrinsic factors in determining the regeneration of the central processes of rat dorsal root ganglion neurons: The influence of a peripheral nerve graft

  1996cited by this paper
• Physical activity, trauma, and ALS: a case‐control study

  1996cited by this paper
• A Sensitive and Reliable Locomotor Rating Scale for Open Field Testing in Rats

  1995cited by this paper
• Regeneration of adult rat sensory axons into intraspinal nerve grafts: promoting effects of conditioning lesion and graft predegeneration.

  1994cited by this paper
• Axotomy-induced neuronal death during development.

  1992cited by this paper
• Adaptation of mammalian skeletal muscle fibers to chronic electrical stimulation.

  1992cited by this paper
• Changes in sizes of cortical and lower motor neurons in amyotrophic lateral sclerosis.

  1991cited by this paper
• Amyotrophic lateral sclerosis: Macro–EMG and twitch forces of single motor units

  1990cited by this paper
• Conditioning lesions of peripheral nerves change regenerated axon numbers.

  1988cited by this paper
• Effects of Conditioning Lesions on Transplant Survival, Connectivity, and Function

  1987cited by this paper
• Effect of exercise on the motor unit

  1986cited by this paper
• Familial adult motor neuron disease: amyotrophic lateral sclerosis

  1986cited by this paper
• Effect of a conditioning lesion on axonal sprout formation at nodes of ranvier

  1985cited by this paper
• Peripheral injury enhances central regeneration of primary sensory neurones

  1984cited by this paper
• Does α-motoneurone size correlate with motor unit type in cat triceps surae?

  1982cited by this paper
• Does alpha-motoneurone size correlate with motor unit type in cat triceps surae?

  1982cited by this paper
• Time course of the conditioning lesion effect on axonal regeneration.

  1980cited by this paper
• Axon outgrowth enhanced by a previous nerve injury.

  1973cited by this paper
• Handbook of Physiology.

  1960cited by this paper

• Ramipril ameliorates endometriosis by inducing oxidative stress-mediated apoptosis in the wistar rat

  2025cites this paper
• Expression of thioredoxin-1 in the ASJ neuron corresponds with and enhances intrinsic regenerative capacity under lesion conditioning in C. elegans

  2023cites this paper
• Expression of thioredoxin-1 in the ASJ neuron corresponds with and 1 enhances intrinsic regenerative capacity under lesion conditioning in 2

  2022cites this paper
• Disease propagation in amyotrophic lateral sclerosis (ALS): an interplay between genetics and environment

  2020cites this paper
• Muscle fiber-type specific terminal Schwann cell pathology leads to sprouting deficits following partial denervation in SOD1G93A mice.

  2020cites this paper
• Mutant SOD1 prevents normal functional recovery through enhanced glial activation and loss of motor neuron innervation after peripheral nerve injury.

  2019cites this paper
• The Impact of Traumatic Brain Injury on Amyotrophic Lateral Sclerosis - From Bedside to Bench.

  2019cites this paper
• An In Vitro Model for Conditioning Lesion Effect

  2018cites this paper
• Crush injury to motor nerves in the G93A transgenic mouse model of amyotrophic lateral sclerosis promotes muscle reinnervation and survival of functionally intact nerve-muscle contacts.

  2018cites this paper
• Developmental and adult-specific processes contribute to de novo neuromuscular regeneration in the lizard tail.

  2018cites this paper
• Roles for the Highwire/Wallenda Pathway in Regenerative and Degenerative Responses to Axonal Injury.

  2013cites this paper
• Clinically definite ALS presenting weeks after mild electric injury: causality or coincidence?

  2012cites this paper
• A Conditioning Lesion Protects Axons from Degeneration via the Wallenda/DLK MAP Kinase Signaling Cascade

  2012cites this paper
• Biomedical engineering strategies for peripheral nerve repair: surgical applications, state of the art, and future challenges.

  2011cites this paper
• Peripheral hyperstimulation alters site of disease onset and course in SOD1 rats.

  2010cites this paper