A(a)LS: Ammonia-induced amyotrophic lateral sclerosis
- Published
- Accepted
- Subject Areas
- Neurology
- Keywords
- ALS, Neurodegeneration, ALS, Ammonia neurotoxicity, Liver, Skeletal muscle, Urea cycle, Metabolic syndrome, Glycolysis, Glutamate, Calcium binding proteins
- Copyright
- © 2015 Parekh
- Licence
- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ PrePrints) and either DOI or URL of the article must be cited.
- Cite this article
- 2015. A(a)LS: Ammonia-induced amyotrophic lateral sclerosis. PeerJ PrePrints 3:e935v1 https://doi.org/10.7287/peerj.preprints.935v1
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. After the 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, ER-stress, CDK5 activation, oxidative/nitrosative stress and neuroinflammation. Furthermore, the regional pattern of calcium binding proteins’ loss, owing to either ER stress and/or impaired oxidative metabolism, determines clinical viabilities of ALS. Most importantly, this new framework can be generalised to explain other neurodegenerative disorders such as Huntington’s disease.
Author Comment
This is a theoretical work on ALS (narrative review). This work answers following key outstanding questions: 1) How does ALS start (pathological trigger)? 2) What are the distal and proximal causes of ALS pathology? and 3) What are the potent treatments? Update 05/19/15: This article is now accepted in F1000 Research, and will soon be undergoing peer review.