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Brain CoA and Acetyl CoA Metabolism in Mechanisms of Neurodegeneration

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Abstract

The processes of biotransformation of pantothenic acid (Pan) in the biosynthesis and hydrolysis of CoA, 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, which is the main substrate of acetylation processes including formation of N-acetyl aspartate and acetylcholine, post-translational modification of histones, predetermines protection of the neurons against degenerative signals and cholinergic neurotransmission. Biochemical mechanisms of neurodegenerative syndromes in the cases of PANK and CoASY defects, and the possibility of correcting of CoA biosynthesis in the models with knockouts of these enzymes have been described. The data of a post-mortem study of the brains from the patients with Huntington’s and Alzheimer’s diseases are presented, proving Pan deficiency in the CNS, which is especially pronounced in the pathognomonic neurostructures. In the frontal cortex of the 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. Redox activity and antioxidant properties of the precursors of CoA biosynthesis were confirmed in vitro with synaptosomal membranes and mitochondria during modeling of aluminum neurotoxicity accompanied by the decrease in the level of CoA in CNS. The ability of CoA biosynthesis precursors to stabilize glutathione pool in neurostructures, in particular, in the hippocampus, is considered as a pathogenetic protection mechanism during exposure to neurotoxins, 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, possible association of oxidative stress and deficiency of Pan (CoA) in neurodegenerative pathology), it seems promising to study bioavailability and biotransformation of Pan derivatives, in particular of D-panthenol, 4′-phospho-pantetheine, its acylated derivatives, and compositions with redox pharmacological compounds, are promising for their potential use as etiopathogenetic agents.

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Abbreviations

ACh:

acetylcholine

AcCoA:

acetyl-CoA

ACSS:

AcCoA synthase

AD:

Alzheimer’s disease

BHB:

β-hydroxybutyrate

CoASY:

CoA-synthetase

COPAN:

CoASY protein-associated neurodegeneration

dPCoA:

dephospho-CoA

GP:

globus pallidus

GPan:

homopantothenate

HD:

Huntington’s disease

NAA:

N-acetylaspartate

NAC:

N-acetylcysteine

NUDT:

nucleoside diphosphatase (Nudix)

Pan:

pantothenic acid

PANK:

pantothenate kinase

PanSH (SS):

pantetheine (pantethine)

PD:

Parkinson’s disease

PKAN:

pantothenate kinase-associated neurodegeneration

PL:

D-panthenol

PPan:

4′-phospho-pantothenic acid

PPanSH(SS):

4′-phospho pantetheine (pantethine)

VNN:

pantetheinase (vanine)

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Authors and Affiliations

  1. Institute of Biochemistry of Biologically Active Substances, National Academy of Sciences of Belarus, 230023, Grodno, Belarus

    Andrey G. Moiseenok & Nina P. Kanunnikova

  2. Yanka Kupala’s Grodno State University, 230023, Grodno, Belarus

    Nina P. Kanunnikova

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  1. Andrey G. Moiseenok
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Contributions

A.G. Moiseenok – conceived the review, wrote Introduction, “Coenzyme a Biosynthesis and Hydrolysis in the CNS”, “CNS-Directed Pantothenic Acid Transport”, “Neuroprotection and Cholinergic Neurotransmission” (in cooperation with N.P. Kanunnikova), “Neurodegenerative Syndromes Associated with CoA Biosynthesis Pathway” sections and concluding remarks; N.P. Kanunnikova – contributed to the sections “Neuroprotection and Cholinergic Neurotransmission”, “Pantothenic Acid Deficiency in Neurodegenerative Diseases”, and concluding remarks, compiled References List and wrote Abstract.

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Correspondence to Andrey G. Moiseenok.

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Authors declare no conflict of interests in financial or any other sphere. This article does not contain any studies with human participants or animals performed by any of the authors.

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Moiseenok, A.G., Kanunnikova, N.P. Brain CoA and Acetyl CoA Metabolism in Mechanisms of Neurodegeneration. Biochemistry Moscow 88, 466–480 (2023). https://doi.org/10.1134/S000629792304003X

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  • DOI: https://doi.org/10.1134/S000629792304003X

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