Visit our Expo - Redox and Inflammation signaling 2012

Session XVII : Cell signaling in health and disease Poster XVII, 15
Nogo-A promotes denervation in an amyotrophic lateral sclerosis model
Anissa Fergani1, Natasa Jokic1, Jose-Luis Gonzalez De Aguilar, Leda Dimou2, Shuo
Lin3, Markus A. Ruegg3, Martin E. Schwab2, Luc Dupuis1 & Jean-Philippe Loeffler1
1Laboratoire de Signalisations Moléculaires et Neurodégénérescence, INSERM U-692,
Université Louis Pasteur, Faculté de Médecine, 11 rue Humann, 67000 Strasbourg,
France,
e-mail: anissa.fergani@neurochem.u-strasbg.fr, jnataly@yahoo.com,
loeffler@neurochem.u-strasbg.fr, 2Brain Research Institute, University of Zurich and
Department of Biology, ETH Zurich, Winterthurerstrasse 190, CH-8057 Zurich,
Switzerland, schwab@hifo.unizh.ch, 3Biozentrum, University of Basel,
Klingelbergstrasse 70, CH-4056 Basel, Switzerland,
e-mail: shuo.lin@unibas.ch, markus-a.ruegg@unibas.ch.
The pathogenesis of ALS still remains unclear. Growing evidence suggests that initial
alterations in skeletal muscle, preceding the onset of disease symptoms, are related to a loss of
neuromuscular junction integrity, axonal degeneration and muscle denervation, rather than
motor neuron death. Our previous studies showed a characteristic expression pattern of the
three major isoforms of the neurite outgrowth inhibitor Nogo (including Nogo-A, -B and -C)
in skeletal muscles of ALS patients and SOD1(G86R) mice. We found that the increased
levels of Nogo-A and Nogo-B, which had been barely detectable in muscles of control
subjects, correlate significantly with the severity of motor impairment of ALS patients, as
determined by the clinically validated ALS functional rating scale. We wished to determine
the impact of knocking down Nogo-A on the progression of ALS pathology in SOD1(G86R)
mice and gain insight into the role of Nogo up-regulation in skeletal muscle. We crossbred
mice knockout for Nogo-A with mice overexpressing the ALS-related mutation G86R, and
followed the survival time. We also performed in vivo skeletal muscle transfection of a vector
expressing Nogo-A in Thy-1/YFP mice, and looked at the morphology of the neuromuscular
junction (NMJ). Double-transgenic G86R/Nogo-A(-/-) mice survived longer than
G86R/Nogo-A(+/+) mice. Transient expression of Nogo-A in skeletal muscle fibers was
sufficient to injury the NMJ by inducing dismantlement of the post-synaptic structures and
loss of pre-synaptic terminals. The ectopic expression of Nogo-A in skeletal muscle initiates a
cascade of events leading to loss of NMJs and denervation. This deletereous effect may be
relevant to ALS since mice suffering from an ALS-like pathology and lacking Nogo-A live
longer. Supported by AFM and ARS.
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