Amyotrophic lateral sclerosis is not only a motor neuron disease: impact of the sympathoadrenal axis

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 SOD1G93A 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 SOD1G93A, 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 sympathoadrenal axis. As disease pathogenesis remains obscure, the search of therapeutic targets to slow disease progression in ALS, remains puzzling.