Brain CoA and acetyl CoA system in mechanisms of neurodegeneration

Abstract

The processes of biotransformation of pantothenic acid (Pan) in the biosynthesis and hydrolysis of CoA, the key role of pantothenate kinase (PANK) and CoA synthetase (CoASY) in the formation of the priority mitochondrial pool of CoA, with a high metabolic turnover of the coenzyme and limited transport of Pan across the blood-brain barrier are considered. The system of acetyl-CoA, a secondary messenger, the main substrate of acetylation processes, including the formation of N-acetylaspartate and acetylcholine, post-translational modification of histones, determines the protection of neurons from degenerative signals and cholinergic neurotransmission. The biochemical mechanisms of neurodegenerative syndromes in PANK and CoASY defects and the possibility of correcting the development of CoA biosynthesis in knockout models for these enzymes are described. The data of a post-mortem study of the brain of patients with Huntington’s and Alzheimer’s diseases are presented, proving Pan deficiency in the CNS, which is especially pronounced in pathognomonic neurostructures. In the frontal cortex of patients with Parkinson’s disease, combined immunofluorescence of anti-CoA- and anti-tau protein was detected, reflecting CoAlation during dimerization of the tau protein and its redox sensitivity. The redox activity and antioxidant properties of the precursors of CoA biosynthesis were confirmed in vitro on synaptosomal membranes and mitochondria in the modeling of aluminum neurotoxicosis, accompanied by a decrease in the level of CoA in the CNS. The ability of CoA biosynthesis precursors to stabilize the glutathione pool in neurostructures, in particular, in the hippocampus, is considered as a pathogenetic protection mechanism when exposed to neurotoxins, the development of neuroinflammation and neurodegeneration, and justifies the combined use of Pan derivatives (for example, D-panthenol) and glutathione precursors (N-acetylcysteine). Taking into account the discovery of new functions of CoA - redox-dependent processes of CoAlation of proteins, the possible association of oxidative stress and deficiency of Pan (CoA) in neurodegenerative pathology, the study of the bioavailability and biotransformation of Pan derivatives, in particular, D-panthenol, 4′-phospho-pantetheine, its acylated derivatives and compositions with redox pharmacological compounds are promising as potential etiopathogenetic agents.