Google Scholar: cites,
Synaptic failure : focus in an integrative view of ALS
Casas Louzao, Caty (Universitat Autònoma de Barcelona. Institut de Neurociències)
Manzano, Raquel (Universidad de Zaragoza)
Vaz, Rita (Universidade de Lisboa. Faculdade de Farmácia)
Osta, Rosario (Universidad de Zaragoza)
Brites, Dora (Universidade de Lisboa. Faculdade de Farmácia)
Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia

Data: 2016
Resum: From early description by Charcot, the classification of the Amyotrophic Lateral Sclerosis (ALS) is evolving from a subtype of Motor Neuron (MN) Disease to be considered rather a multi-systemic, non-cell autonomous and complex neurodegenerative disease. In the last decade, the huge amount of knowledge acquired has shed new insights on the pathological mechanisms underlying ALS from different perspectives. However, a whole vision on the multiple dysfunctional pathways is needed with the inclusion of information often excluded in other published revisions. We propose an integrative view of ALS pathology, although centered on the synaptic failure as a converging and crucial player to the etiology of the disease. Homeostasis of input and output synaptic activity of MNs has been proved to be severely and early disrupted and to definitively contribute to microcircuitry alterations at the spinal cord. Several cells play roles in synaptic communication across the MNs network system such as interneurons, astrocytes, microglia, Schwann and skeletal muscle cells. Microglia are described as highly dynamic surveying cells of the nervous system but also as determinant contributors to the synaptic plasticity linked to neuronal activity. Several signaling axis such as TNF α /TNFR1 and CX3CR1/CX3CL1 that characterize MN-microglia cross talk contribute to synaptic scaling and maintenance, have been found altered in ALS. The presence of dystrophic and atypical microglia in late stages of ALS, with a decline in their dynamic motility and phagocytic ability, together with less synaptic and neuronal contacts disrupts the MN-microglia dialogue, decreases homeostatic regulation of neuronal activity, perturbs "on/off" signals and accelerates disease progression associated to impaired synaptic function and regeneration. Other hotspot in the ALS affected network system is the unstable neuromuscular junction (NMJ) leading to distal axonal degeneration. Reduced neuromuscular spontaneous synaptic activity in ALS mice models was also suggested to account for the selective vulnerability of MNs and decreased regenerative capability. Synaptic destabilization may as well derive from increased release of molecules by muscle cells (e. g. NogoA) and by terminal Schwann cells (e. g. semaphorin 3A) conceivably causing nerve terminal retraction and denervation, as well as inhibition of re-connection to muscle fibers. Indeed, we have overviewed the alterations on the metabolic pathways and self-regenerative capacity presented in skeletal muscle cells that contribute to muscle wasting in ALS. Finally, a detailed footpath of pathologic changes on MNs and associated dysfunctional and synaptic alterations is provided. The oriented motivation in future ALS studies as outlined in the present article will help in fruitful novel achievements on the mechanisms involved and in developing more target-driven therapies that will bring new hope in halting or delaying disease progression in ALS patients.
Nota: Ajuts: This work was supported by grants from Fundació LaMarató-TV3 (110430/31/32) and TERCEL and CIBERNED funds from the Fondo de Investigación Sanitaria of Spain, by FEDER (COMPETE Programme) and Portugal National funds (FCT -Fundação para a Ciência e a Tecnologia --project PTDC/SAU-FAR/118787/2010 to DB and PEst-OE/SAU/UI4013/2011-14 to iMed.ULisboa). ARV is recipient of a Post-Doctoral fellowship (FCT -SFRH/BPD/76590/2011). Authors declare no conflict of interest.
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Matèria: ALS ; Muscle ; Microglia ; Motor neuron ; Synapses ; Neuromuscular junction
Publicat a: Brain plasticity, Vol. 1, issue 2 (2016) , p. 159-175, ISSN 2213-6312

DOI: 10.3233/BPL-140001
PMID: 29765840


17 p, 352.4 KB

El registre apareix a les col·leccions:
Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Neurociències (INc)
Articles > Articles de recerca
Articles > Articles publicats

 Registre creat el 2018-06-04, darrera modificació el 2021-08-08



   Favorit i Compartir