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 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.