title: NO orchestrates the loss of synaptic boutons from adult "sick" motoneurons: modeling a molecular mechanism.
abstract: Synapse elimination is the main factor responsible for the cognitive decline accompanying many of the neuropathological conditions affecting humans. Synaptic stripping of motoneurons is also a common hallmark of several motor pathologies. Therefore, knowledge of the molecular basis underlying this plastic process is of central interest for the development of new therapeutic tools. Recent advances from our group highlight the role of nitric oxide (NO) as a key molecule triggering synapse loss in two models of motor pathologies. De novo expression of the neuronal isoform of NO synthase (nNOS) in motoneurons commonly occurs in response to the physical injury of a motor nerve and in the course of amyotrophic lateral sclerosis. In both conditions, this event precedes synaptic withdrawal from motoneurons. Strikingly, nNOS-synthesized NO is "necessary" and "sufficient" to induce synaptic detachment from motoneurons. The mechanism involves a paracrine/retrograde action of NO on pre-synaptic structures, initiating a downstream signaling cascade that includes sequential activation of (1) soluble guanylyl cyclase, (2) cyclic guanosine monophosphate-dependent protein kinase, and (3) RhoA/Rho kinase (ROCK) signaling. Finally, ROCK activation promotes phosphorylation of regulatory myosin light chain, which leads to myosin activation and actomyosin contraction. This latter event presumably contributes to the contractile force to produce ending axon retraction. Several findings support that this mechanism may operate in the most prevalent neurodegenerative diseases.
authors.affiliation: Grupo de NeuroDegeneración y NeuroReparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Plaza Falla, 9, 11003 Cádiz, Spain. bernardo.moreno@uca.es
authors.forename: Bernardo
authors.initials: B
authors.lastname: Moreno-López
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Sunico
authors.forename: David
authors.initials: D
authors.lastname: González-Forero
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002450:Cell Communication; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure*; D019636:Neurodegenerative Diseases / Q000473:pathology* / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000473:pathology / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase