Anales de la RANM

84 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 AMYOTROPHIC LATERAL SCLEROSIS IS NOT ONLY A MOTOR NEURON DISEASE Fernández A, et al. An RANM. 2022;139(01): 78 - 87 From a pathogenic perspective, ALS is being considered as a multifactorial and multisystem disorder. Multiple signaling pathways have been implicated in MN death. Thus, calcium dyshomeo- stasis and glutamate-dependent excitotoxity, altered mitochondrial calcium handling and augmented oxidative stress have been implicated in disease pathogenesis. More recently, purinergic receptors P2X7 (P2X7Rs) are being explored as a druggable target linked to the neuroinflammatory state underlying ALS pathogenesis (45). The P2X7R is a nonselective ligand-gated ion channel permeable to Na + , Ca 2+ and K + ; this receptor plays a key role in neuroinflamma- tion. Its activation by the high concentrations of ATP released by lesioned neurons results in the assembly of the NLRP3 inflammasome complex in microglia and the subsequent release of pro-inflammatory cytokines such as IL-1β (46). The following observations support the view that P2X7Rs play a major role in ALS pathogenesis: (i) upregulation of P2X7Rs with disease progression in patients; (ii) in vitro challenging with ATP triggers an astrocyte neurotoxic behavior, resulting in MN death that is prevented by P2X7R blocker brilliant Figure 4. Schematic representation of mitochondrial defects observed in the chromaffin cell of a SOD1 G93A mouse. The split-cell drawing represents our observations in the CC of WT mice (upper part) and the transgenic SOD1 G93A mice (bottom). In the cytoplasm of WT CC, there is one healthy mitochondrion with an inset for one cristae magnification (right). In the cristae is depicted the location of the OPA1 protein, the complexes of the electronic transport chain (ETC) and F1F0-ATP synthase. The optimal management of the cristae junction size allows the proton gradient and the main- tenance of mΨ. Otherwise, alterations observed in SOD1 G93A mice are represented in the bottom part (see text for details). The deficiencies here present lead to impairment of the autonomic nervous system, with inability to overcome stressful events, defects in the bioenergetics profile and inefficient energy consumption. These alterations could be crucial for cell-specific and also patient survival, displaying novel pathological mechanisms and therapeutic targets to overcome ALS. (Adapted from Méndez-López et al., 2021). P UR I N E R G I C P2 X 7 R E C E P TO R S : A P O T E N T I A L N EW DRUG G A B L E TA R G E T I N A L S