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- W2204064543 endingPage "119" @default.
- W2204064543 startingPage "119" @default.
- W2204064543 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." @default.
- W2204064543 created "2016-06-24" @default.
- W2204064543 creator A5057379293 @default.
- W2204064543 date "2015-05-14" @default.
- W2204064543 modified "2023-10-01" @default.
- W2204064543 title "A(a)LS: Ammonia-induced amyotrophic lateral sclerosis" @default.
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