Anales de la RANM

79 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 En las CCs encontramos alteraciones drásticas en la cinética del poro de fusión durante la exocitosis, en el ratón SOD1G93A modelo de ELA. Estas alteraciones podrían deberse a la acumulación mitocondrial de la SOD1 mutada, con despola- rización, aumento de la producción de especies reactivas de oxígeno y deficiencia en la fosforilación oxidativa. Finalmente, analizamos algunos datos sobre el potencial terapéutico del compuesto JNJ-47965567, un bloqueante del P2X7R. La administración crónica del compuesto al ratón SOD1G93A retrasó el inicio de la enfermedad en las hembras. En conclusión, la causa de la muerte selectiva de la MN en la ELA continúa siendo desconocida, por lo que resulta difícil identificar nuevas dianas terapéuticas para desarrollar fármacos que enlentezcan su progresión. Por otra parte, parece que la patología se extiende a otras células, particularmente las del eje simpatoadrenal. Amyotrophic lateral sclerosis (ALS), an adult onset and fatal neurodegenerative disease, has as a cardinal pathogenic feature the selective death of motor neurons (MNs) at the cortex, brainstem, and spinal cord. Hence, ALS characteristically presents with muscle weakness, atrophy, and spasticity, leading to paralysis, respiratory insuffi- ciency, and death within 3-5 years of diagnosis. For 25 years, the only available treatment has been riluzole, that interferes with glutamatergic neurotransmission; however, clinical trials (CTs) demonstrated a modest 2-3 months extension of patient survival (1). Recently, the antioxidant edaravone has been approved in Japan and USA, but not in Europe (2). ALS actual prevalence is 4-6/10 5 , 10% of patients having a positive family history (fALS) (3); 25% of fALS patients have mutations in the gene for Cu 2+ / Zn 2+ superoxide dismutase 1 (SOD1) (4). Nearly 200 mutations of the SOD1 gene have been found and, curiously, they do not impair the enzyme activity of SOD1; rather, they elicit its patholog- ical aggregation in the cytosol or mitochondria, leading to MN toxicity (5). Around 40 mutations have also been identified in the TARDBP gene which encodes for the transactive response (TAR)-DNA binding protein 43 (TDP-43) (6). Of interest is the observation that 97% of ALS patients present TDP-43 inclusions. Other relevant mutations have been found in the gene Fused in Sarcoma/ Translocated in Sarcoma (FUS) (7) and the gene hexanucleotide repeats (GGGGCC) in intron1 of chromosome 9 open reading frame 72 (C9orf72) (8). Those ALS mutations are leading causes of disease and based on them, various mouse models have been developed. The first model that was generated, and the most frequently used is the SOD1 G93A mouse (substitution of the glycine at position 93 by alanine) in SOD1 that develop a progressive MN disease resembling the disease progression in humans, with adult onset and reduced lifespan (4). Pathogenically, these mice show early onset microgliosis and astrogli- osis, glutamate-elicited excitotoxicity, deficit in axonal transport, axonal denervation, protein aggregation, aberrant neurofilament processing, and mitochondrial vacuolization. All these processes lead to selective MN loss in the spinal cord, marked wasting, paralysis, and atrophy of the forelimbs and hindlimbs. Thus, this SOD1 G93A mouse model exhibits almost all the hallmarks of ALS (9). In this review we focus on four aspects of the pathogenesis and drug therapy of ALS namely: (i) the hypothesis of disease propagation through the cerebrospinal fluid (CSF); (ii) the distortion of the exocytotic release of neurotransmitters at the sympathoadrenal axis; (iii) the ultrastrural and functional alterations of mitochondria from adrenal medullary chromaffin cells (CCs); and (iv) the purinergic P2X7 receptor (P2X7R) as a novel potential drug target for neuroprotection. This hypothesis deals with the enigma on why MNs become selectively vulnerable and die, giving rise to the progressive evolution of disease pathogen- esis. The pattern of clinical progression suggests that the disease spreads centrifugally from an affected region to an adjacent area; this indicates that a kind of toxic agent generated in the affected area may be released into the extracellular space and the CSF to cause the injury of adjacent MNs. Thus, some authors found that in vitro incubation of neurons or neuronal cell lines with CSF from ALS patients (CSF/ALS) caused cell damage (10), but others did not find such neurotoxic effects (11). INTRODUC TION HYPOTHESIS ON THE ALS PROPAGATION THROUGH THE CEREBROSPINAL FLUID