Age-dependent degeneration of an identified adult leg motor neuron in a SOD1 model of ALS.

Mutations in superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis (ALS) in humans. ALS is a neurodegenerative disease characterized by progressive motor neuron loss leading to paralysis and inevitable death in affected individuals. Using a gene replacement strategy to introduce disease mutations into the orthologous () gene, here, we characterize changes at the neuromuscular junction using longer-lived mutant adults. Homozygous or flies display progressive walking defects with paralysis of the third metathoracic leg. In dissected legs, we assessed age-dependent changes in a single identified motor neuron (MN-I2) innervating the tibia levitator muscle. At adult eclosion, MN-I2 of or flies is patterned similar to wild-type flies indicating no readily apparent developmental defects. Over the course of 10 days post-eclosion, MN-I2 shows an overall reduction in arborization with bouton swelling and loss of the post-synaptic marker () in mutant adults. In addition, increases in polyubiquitinated proteins correlate with the timing and extent of MN-I2 changes. Because similar phenotypes are observed between flies homozygous for either or alleles, we conclude these NMJ changes are mainly associated with loss-of-function. Together these studies characterize age-related morphological and molecular changes associated with axonal retraction in a model of ALS that recapitulate an important aspect of the human disease.This article has an associated First Person interview with the first author of the paper.