Anales de la RANM

78 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 AMYOTROPHIC LATERAL SCLEROSIS IS NOT ONLY A MOTOR NEURON DISEASE: IMPACT OF THE SYMPATHOADRENAL AXIS LA ESCLEROSIS LATERAL AMIOTRÓFICA NO ES SOLO UNA ENFERMEDAD DE LA MOTONEURONA: IMPACTO DEL EJE SIMPATOADRENAL Ana Fernández 1,2 ; Luis Gandía 1,2,4 ; Antonio G. García 1,2,3,4 1 Instituto Teófilo Hernando de I+D del Medicamento 2 Departamento de Farmacología y Terapéutica 3 Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. 4 Fundación Teófilo Hernando, Madrid, Spain. Abstract Amyotrophic lateral sclerosis (ALS), an adult onset, fatal neurodegenerative disease, has as a cardinal pathogenic feature the selective death of motor neurons (MNs) at the cortex, brainstem, and spinal cord. In this review we focus on four aspects: (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 ultrastructural and functional alterations of mitochondria from adrenal medullary chromaffin cells (CCs); and (iv) the purinergic P2X7 receptor (P2X7R) as a potential target for neuroprotection. Concerning disease propagation from one to another area of the central nervous system (CNS), the pattern of clinical progression suggests that the disease spreads centrifugally. This indicates that a kind of toxin agent may be released and propagated through the CSF. In our laboratory we found that CSF from ALS patients exerted toxic effects on cultured cortical MNs. In CCs, we found deep distortions of the exocytotic kinetics and the exocytotic fusion pore in the process of catecholamine release, in the SOD1 G93A mouse model of ALS. Furthermore, we found that these alterations could be related to the accumulation of mutated SOD1 into mitochondria; this resulted in mitochondrial depolarization, excess production of reactive oxygen species and deficiency in oxidative phosphorylation. Finally, we discuss recent data on the potential therapeutic effect of compound JNJ-47965567, a blocker of P2X7Rs known to be central-stage in neuroinflammation. Upon its chronic administration to SOD1 G93A , we found that the compound delayed disease onset but only in females mice. In conclusion, why MN selectively die in ALS disease, remains a mystery; On the other hand, it seems that other cell types are also affected, particularly at the sympathoa- drenal axis. As disease pathogenesis remains obscure, the search of therapeutic targets to slow disease progression in ALS, remains puzzling. Resumen La esclerosis lateral amiotrófica (ELA) es una enfermedad de la edad adulta. Su patogé- nesis se caracteriza principalmente por la muerte selectiva de las motoneuronas (MN) en corteza, tronco del encéfalo y médula espinal. En esta revisión nos centramos en los siguientes aspectos: (i) la hipótesis de la propagación de la enfermedad vía líquido cefalorraquídeo (LCR); (ii) la distorsión de la liberación de neurotransmi- sores a nivel del eje simpatoadrenal; (iii) las alteraciones de las mitocondrias en las células cromafines (CCs) de la médula suprarrenal; (iv) el receptor purinérgico P2X7 (P2X7R) como potencial nueva diana para la neuroprotección. Con respecto a la propagación de la ELA a otras áreas del sistema nervioso central (SNC), el patrón de progresión clínica indica que la enfermedad se extiende centrífu- gamente. Ello sugiere que una toxina del área inicial afectada podría ser vehiculada a otros lugares del SNC. De hecho, en nuestro laboratorio encontramos que el LCR de pacientes con ELA (LCR/ELA) ejercía efectos tóxicos en cultivos de MN. Keywords: Amyotrophic lateral sclerosis; Sympathoadrenal axis; Exocytosis; Cerebrospinal fluid toxicity; Mitochondria disruption; Oxidative stress; P2X7 receptors; neuroinflammation. Palabras clave: Esclerosis lateral Amiotrófica; Eje simpatoadrenal; Exocitosis; Toxicidad en el líquido cefalorraquídeo; Alteración de la mitocondria; Receptor P2X7; Neuroinflamación. Autor para la correspondencia Antonio G. García Tlf.: +34 497 53 84 | E-Mail: agg@uam.es DOI: 10.32440/ar.2022.139.01. rev06 Enviado: 28.09.21 | Revisado: 03.04.22 | Aceptado: 12.04.22 R E V I S I Ó N