Abstract
The lysosomal storage disorders encompass nearly fifty diseases provoked by lack or deficiency of enzymes essential for the breakdown of complex molecules and hallmarked by accumulation in the lysosomes of metabolic residues. Histochemistry and cytochemistry studies evidenced patterns of circadian variation of the lysosomal marker enzymes, suggesting that lysosomal function oscillates rhythmically during the 24-h day. The circadian rhythmicity of cellular processes is driven by the biological clock ticking through transcriptional/translational feedback loops hardwired by circadian genes and proteins. Malfunction of the molecular clockwork may provoke severe deregulation of downstream gene expression regulating a complex array of cellular functions leading to anatomical and functional changes. In this review we highlight that all the genes mutated in lysosomal storage disorders encode circadian transcripts suggesting a direct participation of the biological clock in the pathophysiological mechanisms underlying cellular and tissue derangements hallmarking these hereditary diseases. The 24-h periodicity of oscillation of gene transcription and translation could lead in physiological conditions to circadian rhythmicity of fluctuation of enzyme levels and activity, so that gene transfer could be envisaged to reproduce 24-h periodicity of variation of enzymatic dynamics and circadian rhythmicity could have an impact on the schedule of enzyme replacement therapy.
Competing interests: None declared
Author contributed equally with all other contributors.
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Acknowledgments
The study was supported by the “5x1000” voluntary contribution and by a grant (GM) from the Italian Ministry of Health through Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit (RC1201ME04, RC1203ME46, and RC1302ME31), IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza,” Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy.
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Appendices
Take-Home Message (Synopsis)
The lysosomal storage disorders are caused by mutation of genes whose expression is driven with 24-h periodicity by the biological clock, and the circadian pathways impact the pathophysiological mechanisms, implying the involvement of the temporal dimension in the pathogenesis of these hereditary diseases.
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Gianluigi Mazzoccoli, Tommaso Mazza, Manlio Vinciguerra, Stefano Castellana, and Maurizio Scarpa declare that there are no conflicts of interest with respect to the authorship and/or publication of this article.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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GM conceived the purpose of the review and wrote the article, MV and MS wrote the article, and SC and TM performed bioinformatics analysis and represented scheme and figures.
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Mazzoccoli, G., Mazza, T., Vinciguerra, M., Castellana, S., Scarpa, M. (2014). The Biological Clock and the Molecular Basis of Lysosomal Storage Diseases. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 18. JIMD Reports, vol 18. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_354
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