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Molecular Neurobiology

, Volume 43, Issue 1, pp 41–66 | Cite as

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

  • Bernardo Moreno-López
  • Carmen R. Sunico
  • David González-Forero
Article

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.

Keywords

Nitric oxide synthase Peripheral neuropathy Amyotrophic lateral sclerosis SOD1G93A mice Rho kinase Protein kinase G Soluble guanylyl cyclase Myosin light chain Neurodegenerative diseases 

Notes

Acknowledgments

This work was supported by grants from the Ministerio de Ciencia e Innovación, (SAF2008-01415) and the Consejería de Innovación, Ciencia y Empresa from the Junta de Andalucía (PAI2007-CTS-02606), both co-financed with FEDER funds and the Mútua Madrileña Foundation, Spain. We thank Elaine Lilly, Ph.D. (Writer’s First Aid), for English language revision of this manuscript.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Bernardo Moreno-López
    • 1
  • Carmen R. Sunico
    • 1
  • David González-Forero
    • 1
  1. 1.Grupo de NeuroDegeneración y NeuroReparación (GRUNEDERE), Área de Fisiología, Facultad de MedicinaUniversidad de CádizCádizSpain

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