Anales de la RANM

80 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 our laboratory we tested the effects of CSF from 14 controls (CSF/control) and 29 ALS patients (CSF/ALS) on primary cultures of rat brain cortical MNs. CSF/ALS caused a signif- icant 20% loss of MNs. A reasonable conjec- ture was that these neurotoxic effects could be due to calcium-dependent excitotoxicity elicited by excess glutamate present in CSF/ALS (12). However, we did not find this to be the case as the neurotoxic effects of CSF/ALS were not reversed by the glutamate NMDA receptor blocker MK801 (13). In subsequent experiments, we found that resveratrol, memantine, minocycline and lithium exerted protection against the MN lesion elicited by CSF/ALS. And surprisingly, we also found that riluzole did not afford such protection; in fact, this drug antagonized the neuroprotectant effects of the other compounds (14). This suggested that routine treatment with riluzole of ALS patients enrolled in clinical trials could be a confounding factor in the neurological outcomes attributed to the novel compound being tested. We also attempted to correlate the MN damage elicited by individual CSFs with survival of patients. However, no differences between patients with and without CSF-elicited cytotox- icity exhibited a positive correlation, regarding mean time from symptom onset to diagnosis or to death, as well as time to respiratory assistance or to gastrostomy. However, Cox regression analysis, bulbar onset, gender, or age at onset (but not cytotoxicity) were associated with a lower risk of survival (15). Finally, we analysed the effects of intracerebroven- tricular (ICV) infusion with osmotic minipumps, of cytotoxic CSF/ALS in rats. This led to brain tissue damage similar to that found in sporadic ALS (16). In summary, the studies here commented carried out in the laboratories of Jorge Matías-Guiu and Antonio G. García suggest that ALS pathology could be propagated from its onset at MN nuclei in the cortex, brainstem, or spinal cord, to other areas through as yet unidentified toxic agent that propagates through the CSF. Traditionally, ALS has been considered as an exclusive MN pathology. However, the concept of “non-autonomous motor neuron death” is emerging to imply other neurons and cell types in ALS pathology (17). In fact, various proteins that are altered in ALS undergo ubiquitous alterations. For instance, in the SOD1 G93A mouse model of fALS, the expression of mutated SOD1 G93A occurs in liver and skeletal muscle (18). Curiously, the disease did not develop when the mutant SOD1 was exclusively expressed in either MNs (19) or astrocytes (20). Thus, ALS is being considered as a multisystemic disease with metabolic and physio- logical changes occurring in different peripheral cell types and tissues; they may act mutually and synergistically to provoke ALS onset and to define its time course and severity (21). Therefore, the hypothesis concerning muscle denervation before MN degeneration suggests an initial lesion of the distal axon that progresses in a retrograde “dying back” pattern (22); this opposes the classical view of MN “dying forward” (23). In this context, it is relevant that microRNAs released from peripheral tissues may induce damage at muscle endplates and the spinal cord (24). In a review on the alterations undergone by the exocytotic release of catecholamines in adrenal medullary CCs of transgenic mouse models of neurodegenerative diseases (25) we rose the following hypothesis: the peripheral adrenal medulla senses some of the pathogenic changes undergone by central neurons during the course of neurodegenerative diseases. Those changes may occur in one or more of the following pathways: (i) propagation via the cortico- hypothalamic-sympathoadrenal axis of some of the pathogenic features related to synaptopathies and altered exocytosis occurring centrally ; (ii) distorted regulation at central command neurons that modulate the firing rate of the sympathoad- renal axis; (iii) mutant proteins specific of each neurodegenerative disease that are expressed in CCs and display some functional role in CCs themselves; and (iv) CCs are extremely sensitive to changes in blood pH, hormones and various metabolites and so, the alterations of some of these factors in neurodegenerative diseases may alter CC function. These pathogenic routes will at last lead to altered exocytosis; in so doing, patients suffering a neurodegenerative disease will poorly adapt to stressful conflicts inherent to impaired functional autonomic performance (Fig. 1). This is particularly relevant as ALS patients undergoing sudden death when they are unable to compensate for cardiorespiratory arrest because the failure of the autonomic nervous system. This is especially relevant since ALS patients suffer sudden death when they are unable to compen- sate for cardiorespiratory arrest due to autonomic nervous system failure. In line with this hypothesis are some observations emanating from studies done in ALS patients or in transgenic mouse models of ALS. For example, cardiac sympathetic denervation and alterations at the muscle endplate have been found at early disease stages (26). Subsequent articles also reported early impairment of the autonomic nervous system T H E S YMPAT HOA DR E NA L A X I S I N A L S AND O T H E R NEURODEGENERATIVE DISEASES B E Y OND MO TO R N E UR ON DAMAG E I N A L S PAT HO G E N E S I S