The biological clock and the molecular basis of lysosomal storage diseases

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.