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

Abstract

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.

Circulating Brain‐Enriched MicroRNAs for Detection and Discrimination of Idiopathic and Genetic Parkinson's Disease

“…The functional impact of several of these miRNAs on brain function has been illustrated. Last, we have also included miR‐22‐3p in the analysis as it targets GBA messenger RNA (mRNA) and is highly expressed in the brain …”

“…Last, we have also included miR-22-3p in the analysis as it targets GBA messenger RNA (mRNA) and is highly expressed in the brain. 30…”

“…With respect to PD, the expression levels of many miRNAs are altered in the different regions of PD brain (reviewed in refs. and ) or target PD‐associated proteins including leucine‐rich repeat kinase 2 (LRRK2; miR‐205), SNCA (miR‐7, miR‐153), GBA (miR‐22), Parkinson disease protein 7 (PARK7/DJ‐1; miR‐544), and nuclear receptor subfamily 4 group A2 (NR4A2/nuclear receptor related 1 protein (Nurr1); miR‐132) . In addition, several miRNAs, whose expression is enriched in the brain, target PD‐relevant processes, including mammalian target of rapamycin (mTOR) signaling, autophagy, and inflammation or protect neurons from PD stressors such 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and 6‐hydroxydopamine …”

Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer

“…GBA encodes lysosomal glucocerebrosidase and its mutations are associated with Parkinson's disease. Recently, Tang et al (2017b) demonstrated that GBAP1, a pseudogene of GBA, acted as a ceRNA for GBA by competing with miR-22-3p.…”

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

“…Although formerly considered a noncoding gene, recent data not only show evidence of mRNA expression but that genetic variation in GBAP1 expression could determine expression of the GBA1 gene by acting as a competing antagonist mRNA. 155 Similarly, evidence that variation in upstream promoter regions of the GBA1 gene may modulate GCase activity is available. 156 Interestingly, there is some evidence that the haplotype of the L444P mutation may alter the penetrance of GDassociated alleles, and this may play a significant role in the penetrance of other mutations.…”