Synaptic dysfunction in disease and following injury in the developing and adult nervous system: caveats in the choice of therapeutic intervention.

A cardinal feature of most developmental and adult onset neurodegenerative diseases is the death of specific populations of neurons. Largely as a result of the progress made in elucidating the cellular and molecular mechanisms underlying the neuronal death that occurs during development, approaches ameliorating them often focus on the manipulation of neuronal death pathways. Recent evidence derived from the study of animal models of various neuropathological conditions, however, has revealed that damage to axons and synapses long precedes the activation of death pathways. We recently extended these findings to the most commonly studied animal model of familial amyotrophic lateral sclerosis (fALS). Inhibiting the cell death pathway by deletion of the pro-apoptotic gene Bax completely rescued spinal MNs yet failed to prevent disease in fALS transgenic mice. However, we observed distinct abnormalities within presynaptic terminals of spinal MNs at the neuromuscular junction (NMJ), as well as profound denervation. These results suggest that therapies aimed at preserving the synapse rather than the soma may be more effective at treating these neuropathologies.