TY - JOUR
T1 - Structural and functional evidence for citicoline binding and modulation of 20S proteasome activity
T2 - Novel insights into its pro-proteostatic effect
AU - Sbardella, Diego
AU - Coletta, Andrea
AU - Tundo, Grazia Raffaella
AU - Ahmed, Ikhlas M.M.
AU - Bellia, Francesco
AU - Oddone, Francesco
AU - Manni, Gianluca
AU - Coletta, Massimo
N1 - Funding Information:
Special thanks are due to Omikron Italia SrL for a liberal donation. The financial support from the INCIPIT-COFUND project co-funded by HORIZON 2020/Marie Sklodowska Curie Actions and from the Italian Ministery of University and Research (PRIN 2017SNRXH3) is also acknowledged. The authors also thank Dr. Jennifer C. Lee (NIH-Laboratory of molecular biophysics, Bethesda) and Dr. Michel Goedert (MRC Laboratory of Molecular Biology, Cambridge) for kindly providing the αSyn expression vector.
Publisher Copyright:
© 2020 Elsevier Inc.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7
Y1 - 2020/7
N2 - Citicoline or CDP-choline is a drug, made up by a cytidine 5′-diphosphate moiety and choline, which upon adsorption is rapidly hydrolyzed into cytidine 5′-diphosphate and choline, easily bypassing the blood–brain barrier. Once in the brain, these metabolites are used to re-synthesize citicoline in neurons and in the other cell histo-types which uptake them. Citicoline administration finds broad therapeutic application in the treatment of glaucoma as well as other retinal disorders by virtue of its safety profile and neuro-protective and neuroenhancer activity, which significantly improves the visual function. Further, though supported by limited clinical studies, this molecule finds therapeutic application in neurodegenerative disease, delaying the cognitive decline in Alzheimer's Disease (AD) and Parkinson's Disease (PD) subjects. In this work we show that citicoline greatly affects the proteolytic activity of the 20S proteasome on synthetic and natural substrates, functioning as a bimodal allosteric modulator, likely binding at multiple sites. In silico binding simulations identify several potential binding sites for citicoline on 20S proteasome, and their topology envisages the possibility that, by occupying some of these pockets, citicoline may induce a conformational shift of the 20S proteasome, allowing to sketch a working hypothesis for the structural basis of its function as allosteric modulator. In addition, we show that over the same concentration range citicoline affects the distribution of assembled proteasome populations and turn-over of ubiquitinated proteins in SH-SY5Y and SK-N-BE human neuroblastoma cells, suggesting its potential role as a regulator of proteostasis in nervous cells.
AB - Citicoline or CDP-choline is a drug, made up by a cytidine 5′-diphosphate moiety and choline, which upon adsorption is rapidly hydrolyzed into cytidine 5′-diphosphate and choline, easily bypassing the blood–brain barrier. Once in the brain, these metabolites are used to re-synthesize citicoline in neurons and in the other cell histo-types which uptake them. Citicoline administration finds broad therapeutic application in the treatment of glaucoma as well as other retinal disorders by virtue of its safety profile and neuro-protective and neuroenhancer activity, which significantly improves the visual function. Further, though supported by limited clinical studies, this molecule finds therapeutic application in neurodegenerative disease, delaying the cognitive decline in Alzheimer's Disease (AD) and Parkinson's Disease (PD) subjects. In this work we show that citicoline greatly affects the proteolytic activity of the 20S proteasome on synthetic and natural substrates, functioning as a bimodal allosteric modulator, likely binding at multiple sites. In silico binding simulations identify several potential binding sites for citicoline on 20S proteasome, and their topology envisages the possibility that, by occupying some of these pockets, citicoline may induce a conformational shift of the 20S proteasome, allowing to sketch a working hypothesis for the structural basis of its function as allosteric modulator. In addition, we show that over the same concentration range citicoline affects the distribution of assembled proteasome populations and turn-over of ubiquitinated proteins in SH-SY5Y and SK-N-BE human neuroblastoma cells, suggesting its potential role as a regulator of proteostasis in nervous cells.
KW - Citicoline
KW - Glaucoma
KW - Proteasome
KW - Proteostasis
KW - Retina
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U2 - 10.1016/j.bcp.2020.113977
DO - 10.1016/j.bcp.2020.113977
M3 - Article
C2 - 32298691
AN - SCOPUS:85083590681
VL - 177
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
M1 - 113977
ER -