Levels of a protein called progranulin (PGRN) are significantly lower in the blood of Gaucher disease (GD) patients compared to the general population, according to a study conducted by a team of international researchers. These findings have potential implications not only to further the knowledge of GD development, but also for possible new therapeutic avenues.
It is already known that Gaucher disease is caused by mutations in a gene called GBA1, which results in reduced activity of the β-glucocerebrosidase (GCase) enzyme. This causes the glucosylceramide (β-GlcCer), the substrate of GCase, to accumulate inside cells, leading to Gaucher disease.
This study, led by Dr. Chuan-ju Liu of New York University School of Medicine, demonstrates an association between the PGRN gene and GD, which was previously unknown.
“These findings not only provide new insight into the pathogenesis of GD, but may also have implications for diagnosis and alternative targeted therapies for GD,” the authors wrote.
The researchers first measured the levels of PGRN in the blood of 115 Gaucher disease patients and 99 healthy volunteers and found that levels were significantly lower in Gaucher patients compared to healthy controls — around 96 ng/mL in patients versus 165 ng/mL in controls.
Next, the researchers extracted DNA from the blood of 40 Gaucher disease patients and sequenced it. They identified four single nucleotide polymorphisms (or single letter changes in the DNA code) and three point mutations in the PGRN gene in the DNA of the patients.
They then analyzed the DNA of 161 GD patients and 142 healthy volunteers, specifically looking at the four single nucleotide polymorphisms that they had identified.
They saw that the four single nucleotide polymorphism sites were significantly higher in frequency in Gaucher patients compared to healthy volunteers.
They concluded that analyzing the levels of PGRN protein in the blood or mutations in the PGRN gene might represent an alternative approach for the diagnosis of Gaucher disease.
The researchers then turned to a mouse model to further explain the role that the PGRN gene plays in GD. When they knocked down the PGRN gene in mice, and then induced lung inflammation, they saw that the animals developed signs similar to the ones seen in Gaucher disease patients. These included typical Gaucher-like cells in the lungs, spleen, and bone marrow. The same effect was also seen when the PGRN-deficient mice aged.
In further analysis, the researchers demonstrated that although PGRN is not associated with the function of GCase, it is required for the correct localization of GCase inside lysosomes (or small pouches full of enzymes found inside cells) and its deficiency leads to GCase accumulation in the cytoplasm.
Finally, when the researchers injected a healthy copy of the PGRN gene inside the mice, they saw that these Gaucher-like cells disappeared. They demonstrated the same effect in an established animal model of Gaucher disease as well as in patient cells grown in the laboratory. They concluded that PGRN has a therapeutic effect in several animal models of Gaucher disease and human fibroblasts from GD patients.
The study, titled “Association Between Progranulin and Gaucher Disease,” was published in EBioMedicine.
