Figure 1.

Model for motoneuron degeneration and the underlying signaling network in SMA. Motoneuron loss observed in post mortem analyses is preceded by a functional degeneration of central synapses and the neuromuscular junction. The subsequent axonal damage induces a chromatolytic phenotype of the motoneurons. During disease progression those processes become less reversible indicated by a reduced regenerative capacity. This is reflected by a growing network of dysregulated signaling nodes with an increased fraction of SMN-irreversible (black) vs. SMN-reversible (blue) signaling mediators. SMN-restoration restores blue nodes only. The relative number of SMN-restorable nodes becomes reduced over time as illustrated in this hypothetical scheme. Highly connected SMN-irreversible (black) nodes may be potent treatment targets (arrow). Those nodes may be critical regulators for a module involved in a specific degenerative process.