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.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most feared, frequent, flummoxing and fatal motor neuron disease[1,2,3]
Ammonia neurotoxicity: hypothesis and evidence Together, these findings provide a compelling rationale for a new hypothesis
Compared to skeletal muscle, the extraocular muscles (EOMs) have slow metabolism characterised by low complexes I and IV activities (~50%) yet elevated mitochondria density with increased complex I and IV levels (30% to 2 times)—explaining why parvalbumin and calbindin levels remain relatively unaffected in EOMs205,216,217
Summary
Amyotrophic lateral sclerosis (ALS) is the most feared, frequent, flummoxing and fatal motor neuron disease[1,2,3]. Central to this explanation is the notion that ALS is a neurological disease of metabolic origin—resembling hepatocerebral degeneration[223] This explanation posits that ALS pathology involves the interplay of two critical factors: 1) chronic hyperammonia caused by imbalanced interogan ammonia metabolism, mainly due to muscle and liver pathology (Figure 1 and Figure 2) altered CaBPs homeostasis, mainly due to increased ER stress and impaired mitochondrial respiration (Figure 1). Considering all these together in sequence, impaired fast twitch skeletal muscle carbohydrate metabolism activates purinergic and amino acid catabolism, leading to a release of ammonia, a neurotoxin. Grant information The author(s) declared that no grants were involved in supporting this work
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