Anales de la RANM

81 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 in ALS (27); such alterations were revealed as subclinical early dysautonomic events at cardio- vascular, salivary, skin, lachrymal and gastro- intestinal functions. These alterations have also been disclosed in SOD1 G93A mice (28). In line with these observations is the augmented noradrenaline levels in blood and CSF of ALS patients (29) and in ALS mouse models (30). This is also in line with the presence of sympathetic hyperactivity in ALS patients (26); however, in another report, no change in sympathetic activity was reported (31). Later studies found that ALS patients were hypermeta- bolic, involving mitochondrial energy production and sympathoadrenal activation (32). Finally, a study in the SOD1 G93A mouse model of ALS found progressive alterations in the axonal transport of neurosecretory products from neuronal perikarya to nerve terminals (33). Figure 1. Schematic representation sum- marizing the hypothesis proposed in the text. Normal stress response (left hand diagram) implies the processing of the stressor by the cortex, which regulates sympathetic nervous system activity through the hypothalamus, including secretion of catecholamines and other neurohormones by the CCs of the adre- nal medulla. Alterations occurring in the brain of mice, carrying a gene mu- tation linked to familial neurodegenera- tive diseases, may be “propagated” peri- pherally through the sympatho-adrenal axis (1) or affect command neurons that control autonomic nervous system tone and response to stressors (2). Other me- tabolites generated by CNS malfunction may also diffuse through blood circula- tion creating a pathogenic micro-envi- ronment inducing long-time deleterious changes in CCs altering the stimulus- secretion coupling process (3). Mutated proteins expressed in chromaffin cells themselves may also alter the exocyto- tic fusion pore and the quantal size of single secretory vesicles thus making response to stress and the preservation of the body homeostasis inefficient (4). One or various of these phenomena ac- ting together may translate into the cli- nic as a higher vulnerability of patients suffering of neurodegenerative disease. MIT, mitochondria; ER, endoplasmic reticulum; VACCs, voltage-activated calcium channels; V, large dense cored vesicles; N, nucleus. (Adapted from ( de Diego & Garcia, 2018).