NO Orchestrates the Loss of Synaptic Boutons from Adult “Sick” Motoneurons: Modeling a Molecular Mechanism

摘要: Synapse elimination is the main factor responsible for cognitive decline accompanying many of neuropathological conditions affecting humans. Synaptic stripping motoneurons also a common hallmark several motor pathologies. Therefore, knowledge molecular basis underlying this plastic process central interest development new therapeutic tools. Recent advances from our group highlight role nitric oxide (NO) as key molecule triggering synapse loss in two models De novo expression neuronal isoform NO synthase (nNOS) commonly occurs response to physical injury nerve and course amyotrophic lateral sclerosis. In both conditions, event precedes synaptic withdrawal motoneurons. Strikingly, nNOS-synthesized “necessary” “sufficient” induce detachment The mechanism involves paracrine/retrograde action on pre-synaptic structures, initiating downstream signaling cascade that includes sequential activation (1) soluble guanylyl cyclase, (2) cyclic guanosine monophosphate-dependent protein kinase, (3) RhoA/Rho kinase (ROCK) signaling. Finally, ROCK promotes phosphorylation regulatory myosin light chain, which leads actomyosin contraction. This latter presumably contributes contractile force produce ending axon retraction. Several findings support may operate most prevalent neurodegenerative diseases.