Synaptic sprouting increases the uptake capacities of motoneurons in amyotrophic lateral sclerosis mice

Using adenoviruses encoding reporter genes as retrograde tracers, we assess ed the capacity of motoneurons to take up and retrogradely transport adenov iral particles injected into the muscles of transgenic mice expressing the G93A human superoxide dismutase mutation, a model of amyotrophic lateral sc lerosis. Surprisingly. transgene expression in the motoneurons was signific antly higher in symptomatic mice than in control or presymptomatic mice. Us ing botulinum toxin to induce nerve sprouting at neuromuscular junctions, w e showed that the unexpectedly high level of motoneurons retrograde transdu ction results, at least in part, from newly acquired uptake properties of t he sprouts. These findings demonstrate the remarkable uptake properties of amyotrophic lateral sclerosis motoneurons in response to denervation and th e rationale of using intramuscular injections of adenoviruses to overexpres s therapeutic proteins in motor neuron diseases.