Epigenetic landscape in lysosomal storage disorders: mechanisms and modulation.

Lysosomal storage disorders (LSDs) are rare substrate-accumulating diseases primarily characterized by mutations in genes encoding proteins involved in lysosomal function, most of which have enzymatic activity. Resulting lysosomal dysfunction leads to the overaccumulation of non- or partially degraded substrates. While it is true that enzyme deficiency is the primary cause of LSDs, the epigenetic alterations in DNA methylation, miRNA expression, and histone modifications appear to be critical mechanisms involved in the pathogenesis of LSDs. As epigenetic marks are, in most cases, reversible, their study becomes vital to developing strategies aimed at reversing epigenome alterations. Although classical therapeutic alternatives aim to recover the lysosomal function by restoring the protein expression lost, the use of modifiers able to repair the epigenetic modifications in LSDs may become a promising strategy. This manuscript explores the most recent evidence on the epigenetic alterations in LSDs. It also discusses their modulation through epigenetic modulators, a novel and intriguing approach to treat LSDs, as well as the potential of the CRISPR/Cas9 system.