4.5 Article

Identification of miRNAs that modulate glucocerebrosidase activity in Gaucher disease cells

Journal

RNA BIOLOGY
Volume 11, Issue 10, Pages 1291-1300

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/15476286.2014.996085

Keywords

Gaucher Disease; GBA; GCase; glucocerebrosidase; mimics; miRNA; screen

Funding

  1. Intramural Research Programs of National Human Genome Research Institute
  2. RNAi Screening Facility of National Center for Advancing Translational Sciences
  3. National Institutes of Health
  4. Brazilian Federal Agency for Support and Evaluation of Graduate Education - CAPES
  5. Fulbright Brazil

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Gaucher disease is an autosomal recessive disorder caused by deficiency of the enzyme glucocerebrosidase. Although it is a monogenic disease, there is vast phenotypic heterogeneity, even among patients with the same genotype. MicroRNAs (miRNAs) are small non-coding RNAs involved in many biological processes and diseases. To determine whether miRNAs can affect glucocerebrosidase activity, we performed a screen of 875 different miRNA mimics. The screen was performed using Gaucher fibroblasts, and glucocerebrosidase activity was used as the initial outcome parameter. We found several miRNAs that either up- or down-regulated glucocerebrosidase activity. In follow-up assays, we confirmed that one specific miRNA (miR-127-5p) down-regulated both glucocerebrosidase activity and protein levels by down-regulation of LIMP-2, the receptor involved in proper trafficking of glucocerebrosidase from the endoplasmic reticulum to the lysosome. A conditioned media assay demonstrated that cells treated with this miRNA secreted glucocerebrosidase into the extracellular environment, supporting impaired LIMP-2 function. Two other miRNAs, miR-16-5p and miR-195-5p, were found to up-regulate glucocerebrosidase activity by greater than 40% and to enhance expression and protein levels of the enzyme. In conclusion, we show that miRNAs can alter glucocerebrosidase activity in patient cells, indicating that miRNAs can potentially act as modifiers in Gaucher disease.

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