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Mutations in the  GBA  gene, encoding lysosomal glucocerebrosidase, represent the major predisposing factor for Parkinson’s disease (PD), and modulation of the glucocerebrosidase activity is an emerging PD therapy. However, little is known about mechanisms regulating  GBA  expression. We explored the existence of a regulatory network involving  GBA , its expressed pseudogene  GBAP1 , and microRNAs. The high level of sequence identity between  GBA  and  GBAP1  makes the pseudogene a promising competing-endogenous RNA (ceRNA), functioning as a microRNA sponge. After selecting microRNAs potentially targeting both transcripts, we demonstrated that miR-22-3p binds to and down-regulates  GBA  and  GBAP1 , and decreases their endogenous mRNA levels up to 70%. Moreover, over-expression of  GBAP1  3′-untranslated region was able to sequester miR-22-3p, thus increasing  GBA  mRNA and glucocerebrosidase levels. The characterization of  GBAP1  splicing identified multiple out-of-frame isoforms down-regulated by the nonsense-mediated mRNA decay, suggesting that  GBAP1  levels and, accordingly, its ceRNA effect, are significantly modulated by this degradation process. Using skin-derived induced pluripotent stem cells of PD patients with  GBA  mutations and controls, we observed a significant  GBA  up-regulation during dopaminergic differentiation, paralleled by down-regulation of miR-22-3p. Our results describe the first microRNA controlling  GBA  and suggest that the  GBAP1  non-coding RNA functions as a  GBA  ceRNA.

The GBAP1 pseudogene acts as a ceRNA for the glucocerebrosidase gene GBA by sponging miR-22-3p