Abstract
BackgroundAmyotrophic 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 FindingsTo 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/SignificanceThese 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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motoneurons
To determine the effects of a conditioning lesion on disease progression in fALSG93A rats we crushed the tibial nerve at age 10 weeks
We have shown that a conditioning lesion in fALSG93A rats reduced motor functional decline, motoneuron loss, axonopathy, and muscle denervation in a focal manner
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motoneurons. For more than a decade Riluzole has remained the only medication proven to slow, albeit very modestly, the progression of ALS. This lack of success in ALS therapeutic development has not been due to lack of effort. Amyotrophic Lateral Sclerosis (ALS) is neurodegenerative disease characterized by muscle weakness and atrophy due to progressive motoneuron loss. 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
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