A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a dreadful, devastating and incurable motor neuron disease. Aetiologically, it is a multigenic, multifactorial and multiorgan disease. Despite intense research, ALS pathology remains unexplained. Following extensive literature review, this paper posits a new integrative explanation. This framework proposes that ammonia neurotoxicity is a main player in ALS pathogenesis. According to this explanation, a combination of impaired ammonia removal— mainly because of impaired hepatic urea cycle dysfunction—and increased ammoniagenesis— mainly because of impaired glycolytic metabolism in fast twitch skeletal muscle—causes chronic hyperammonia in ALS. In the absence of neuroprotective calcium binding proteins (calbindin, calreticulin and parvalbumin), elevated ammonia—a neurotoxin—damages motor neurons. Ammonia-induced motor neuron damage occurs through multiple mechanisms such as macroautophagy-endolysosomal impairment, endoplasmic reticulum (ER) stress, CDK5 activation, oxidative/nitrosative stress, neuronal hyperexcitability and neuroinflammation. Furthermore, the regional pattern of calcium binding proteins’ loss, owing to either ER stress and/or impaired oxidative metabolism, determines clinical variability of ALS. Most importantly, this new framework can be generalised to explain other neurodegenerative disorders such as Huntington’s disease and Parkinsonism.

Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors

“…An ammonia-induced neurotoxicity model uncovered potential therapeutic strategies ( Hadjihambi et al, 2014 ). Elevated ammonia levels damage motor neurons through numerous means, including endoplasmic reticulum (ER) stress, cyclin-dependent kinase 5 activation, macroautophagy-endolysosomal pathway impairment, oxidative and nitrosative stress, neuronal hyperexcitability, and neuroinflammation ( Parekh, 2015 ). In order to produce neurotoxicity, ammonia modulates glutamate receptors and activates NMDARs which in turn leads to the following: (i) adenosine triphosphate (ATP) is depleted in the brain, causing glutamate release; (ii) calcineurin and dephosphorylation are activated and Na + /K + -ATPase is activated in the brain, increasing ATP consumption; (iii) mitochondrial function and calcium homeostasis are impaired at different levels, thus reducing ATP synthesis; (iv) calpain activation degrades microtubule-associated protein-2, thus altering the microtubular network; and (v) nitric oxide (NO) formation rises, reducing the activity of glutamine synthetase, thus decreasing the elimination of ammonia in the brain ( Monfort et al, 2002 ; Kosenko et al, 2004 ).…”

“…Based on the complexity of the mechanistic progression of NDDs, elucidating the proper disease pathophysiology and therapeutics of NDDs remains a major challenge. Recently, many neurotoxic agents have been employed in experiments in order to explore cellular functions and dysfunctions ( Kumar and Kumar, 2010 ; van der Star et al, 2012 ; Abbasi et al, 2013 ; Jiang et al, 2015 ; Parekh, 2015 ; Ahmad et al, 2017 ; Kim et al, 2017 ). Their correlation with pathological characteristics of diseases via the utilization of neurotoxic agent-induced models is a helpful way to screen and discover potential therapeutic drugs for NDDs.…”

Effects of a high protein diet and liver disease in an in silico model of human ammonia metabolism

“…Increased blood ammonia levels are a causative agent in hepatic encephalopathy (HE) [16], but increased ammonia levels have also been implicated in other neural disorders such as Alzheimer’s disease [17], amyotrophic lateral sclerosis [18], and Huntington’s disease [19]. HE results from liver damage leading to cognitive impairment.…”

Medium-Chain Fatty Acids Rescue Motor Function and Neuromuscular Junction Degeneration in a Drosophila Model of Amyotrophic Lateral Sclerosis

“…Hyperammonaemia is also known to induce mitochondrial dysfunction in animal models, resulting in neuronal cell death [63]. Importantly, ammonia neurotoxicity has been proposed as a key feature in ALS pathogenicity [64]. Evidence of hyperammonaemia in ALS has been provided by a clinical study, noting that levels of ammonia correlate with disease duration [65]; this link was further confirmed in an SOD1 mouse model of ALS [66].…”