Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut Microbiome, and Muscle Interactions via the Mitochondrial Melatonergic Pathway, with Disruption by Glyphosate-Based Herbicides

Abstract

The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage of ALS patients having a known genetic risk factor. The article looks to integrate wider bodies of data on the biological underpinnings of ALS, highlighting the integrative role of alterations in the mitochondrial melatonergic pathways and systemic factors regulating this pathway across a number of crucial hubs in ALS pathophysiology, namely glia, gut, and the muscle/neuromuscular junction. It is proposed that suppression of the mitochondrial melatonergic pathway underpins changes in muscle brain-derived neurotrophic factor, and its melatonergic pathway mimic, N-acetylserotonin, leading to a lack of metabolic trophic support at the neuromuscular junction. The attenuation of the melatonergic pathway in astrocytes prevents activation of toll-like receptor agonists-induced pro-inflammatory transcription factors, NF-kB, and yin yang 1, from having a built-in limitation on inflammatory induction that arises from their synchronized induction of melatonin release. Such maintained astrocyte activation, coupled with heightened microglia reactivity, is an important driver of motor neuron susceptibility in ALS. Two important systemic factors, gut dysbiosis/permeability and pineal melatonin mediate many of their beneficial effects via their capacity to upregulate the mitochondrial melatonergic pathway in central and systemic cells. The mitochondrial melatonergic pathway may be seen as a core aspect of cellular function, with its suppression increasing reactive oxygen species (ROS), leading to ROS-induced microRNAs, thereby altering the patterning of genes induced. It is proposed that the increased occupational risk of ALS in farmers, gardeners, and sportsmen and women is intimately linked to exposure, whilst being physically active, to the widely used glyphosate-based herbicides. This has numerous research and treatment implications.

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

“…A plethora of studies have highlighted the role of pancreatic β-cell mitochondria as a crucial aspect of T1DM pathophysiology. Recent work indicates that the mitochondrial melatonergic pathway may be a core aspect of mitochondrial function, with relevance across a host of diverse medical conditions, including Alzheimer’s disease [ 97 , 98 ], multiple sclerosis [ 99 , 100 ], glioblastoma [ 101 , 102 ], breast cancer [ 103 , 104 ], depression [ 105 , 106 ], and amyotrophic lateral sclerosis [ 7 , 107 , 108 ]. Integrating the melatonergic pathway into the biological underpinnings of T1DM allows for the inclusion of previous disparate bodies of data, providing a conceptualization of T1DM that has treatment and future research implications.…”

“…The tryptophan–melatonin pathway is evident in cells across body organs and tissues, with relevance to a host of diverse medical conditions, including depression [ 36 ], amyotrophic lateral sclerosis [ 7 ], cancers [ 113 ] and dementia [ 97 ]; see Figure 1 . Most tryptophan is derived from dietary sources, although the shikimate pathway in the human gut microbiome is a relevant provider of aromatic amino acids, including tryptophan, as well as tyrosine and phenylalanine [ 7 ]. The shikimate pathway is proposed below to be a significant aspect of T1DM pathophysiology.…”

“…TrkB signaling is complicated by the existence of full-length (TrkB-FL) and truncated (TrkB-T1) forms. Generally, TrkB-FL is associated with trophic signaling, whilst TrkB-T1 is linked to cellular dysfunction and apoptosis arising from lost trophic signaling, as exemplified in motor neuron loss in amyotrophic lateral sclerosis [ 7 ]. However, this does not seem to be the case in murine pancreatic β-cells [ 118 ].…”

“…Are pancreatic β-cells competitively eliminated within an altered intercellular homeostasis in islets? During brain development and in amyotrophic lateral sclerosis motor neuron loss, the induction of the truncated TrkB-T1 seems important to prevent BDNF and NAS trophic and metabolic support to cells [ 7 ]. Data in pancreatic β-cells do show BDNF, via TrkB-T1, to provide trophic support to pancreatic β-cells [ 118 ], although other data show that trophic support in pancreatic β-cells is provided mainly by TrkB-FL [ 122 ].…”

“…As T1DM is associated with functional disturbances in many organs, it is linked to an elevated risk of numerous other medical conditions, including dementia [ 2 , 3 ], cardiovascular disorders, kidney disorders, retinopathy, neuropathy, hypertension, lung disorders, obesity, and amyotrophic lateral sclerosis (ALS) [ 4 ], as well as bacterial and fungal infections [ 5 , 6 ]. As all these comorbidities show alterations in the gut microbiome and gut permeability [ 7 , 8 ], the gut dysbiosis evident in T1DM is an important mediator of its pathophysiological associations of these comorbidities [ 9 ].…”