Structural and functional evidence for citicoline binding and modulation of 20S proteasome activity: Novel insights into its pro-proteostatic effect

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  • Diego Sbardella, IRCCS Fondazione G.B. Bietti per lo studio e la ricerca in oftalmologia - Roma
  • ,
  • Andrea Coletta
  • ,
  • Grazia Raffaella Tundo, Universita degli Studi di Roma Tor Vergata
  • ,
  • Ikhlas M.M. Ahmed, CNR
  • ,
  • Francesco Bellia, CNR
  • ,
  • Francesco Oddone, IRCCS Fondazione G.B. Bietti per lo studio e la ricerca in oftalmologia - Roma
  • ,
  • Gianluca Manni, Universita degli Studi di Roma Tor Vergata
  • ,
  • Massimo Coletta, Universita degli Studi di Roma Tor Vergata

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.

Original languageEnglish
Article number113977
JournalBiochemical Pharmacology
Volume177
Number of pages17
ISSN0006-2952
DOIs
Publication statusPublished - 2020

    Research areas

  • Citicoline, Glaucoma, Proteasome, Proteostasis, Retina

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