Synaptic sprouting increases the uptake capacities of motoneurons in amyotrophic lateral sclerosis mice.
Using adenoviruses encoding reporter genes as retrograde tracers, we assessed the capacity of motoneurons to take up and retrogradely transport adenoviral particles injected into the muscles of transgenic mice expressing the G93A human superoxide dismutase mutation, a model of amyotrophic lateral sclerosis. Surprisingly, transgene expression in the motoneurons was significantly higher in symptomatic mice than in control or presymptomatic mice. Using botulinum toxin to induce nerve sprouting at neuromuscular junctions, we showed that the unexpectedly high level of motoneurons retrograde transduction results, at least in part, from newly acquired uptake properties of the sprouts. These findings demonstrate the remarkable uptake properties of amyotrophic lateral sclerosis motoneurons in response to denervation and the rationale of using intramuscular injections of adenoviruses to overexpress therapeutic proteins in motor neuron diseases.
Millecamps
S
S
Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Centre National de la Recherche Scientifique FRE2360, Bât CERVI, Hôpital Pitié Salpêtrière, 75013 Paris, France.
Nicolle
D
D
Ceballos-Picot
I
I
Mallet
J
J
Barkats
M
M
D000256:Adenoviridae; D000818:Animals; D001933:Brain Stem / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D009046:Motor Neurons / Q000201:enzymology / Q000502:physiology*; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation / Q000503:physiopathology*; D020125:Mutation, Missense; D009469:Neuromuscular Junction / Q000502:physiology / Q000503:physiopathology*; D012016:Reference Values; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D014059:Tongue / Q000294:innervation; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
D008156:Luciferases; D013482:Superoxide Dismutase; D001616:beta-Galactosidase