000109129 001__ 109129 000109129 005__ 20211220115840.0 000109129 0247_ $$2doi$$a10.3233/BPL-140001 000109129 0248_ $$2sideral$$a125179 000109129 037__ $$aART-2016-125179 000109129 041__ $$aeng 000109129 100__ $$aCasas, Caty 000109129 245__ $$aSynaptic Failure: Focus in an Integrative View of ALS 000109129 260__ $$c2016 000109129 5060_ $$aAccess copy available to the general public$$fUnrestricted 000109129 5203_ $$aFrom 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 TNFα/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. 000109129 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttp://creativecommons.org/licenses/by-nc/3.0/es/ 000109129 655_4 $$ainfo:eu-repo/semantics/review$$vinfo:eu-repo/semantics/publishedVersion 000109129 700__ $$0(orcid)0000-0002-7477-8742$$aManzano, Raquel 000109129 700__ $$aVaz, Rita 000109129 700__ $$0(orcid)0000-0001-5687-6704$$aOsta, Rosario$$uUniversidad de Zaragoza 000109129 700__ $$aBrites, Dora 000109129 7102_ $$11001$$2420$$aUniversidad de Zaragoza$$bDpto. Anatom.,Embri.Genét.Ani.$$cÁrea Genética 000109129 773__ $$g1, 2 (2016), 159-175$$pBrain plast.$$tBrain Plasticity$$x2213-6304 000109129 8564_ $$s358191$$uhttps://zaguan.unizar.es/record/109129/files/texto_completo.pdf$$yVersión publicada 000109129 8564_ $$s2441609$$uhttps://zaguan.unizar.es/record/109129/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000109129 909CO $$ooai:zaguan.unizar.es:109129$$particulos$$pdriver 000109129 951__ $$a2021-12-20-10:40:43 000109129 980__ $$aARTICLE