The researches find that the inherited disorders teach scientists about more common health problems like fibrosis? Plenty, based on research led by St. Jude Children’s Research Hospital scientists that appears today in the journal Science Advances. The investigators have discovered an association between a deficiency in the enzyme neuraminidase 1 (NEU1) and the build-up of connective tissue (fibrosis) in organs such as the muscle, kidney, liver; heart and lungs. Fibrosis includes life-threatening conditions such as idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis
Mutations in the NEU1 gene cause the lysosomal storage disease sialidosis; which belongs to a large group of relate pediatric diseases. This is the first time NEU1 has been associate with fibrotic conditions.” Corresponding author Alessandra d’Azzo, Ph.D., member and endow chair of the St. Jude Department of Genetics NEU1 is an important enzyme that breaks down sugar-containing molecules in many cells of the body; but it has not really been on the radar for adult health problems.
Based on these findings, it is tantalizing to hypothesize that NEU1 expression levels may help identify individuals at risk for fibrosis or inform their prognosis; particularly when information about the cause or possible treatment is lacking,” she said. Fibrosis results when excess connective tissue is produced and accumulates and disrupts normal function of the muscle, lungs, liver, heart and other tissues. Connective tissue is produce in part by fibroblast cells.
Excess connective tissue
The findings build on earlier research from d’Azzo’s laboratory. That work centered on mice that lacked the Neu1 gene. The mice developed muscle atrophy when connective tissue proliferated and invaded muscle. In this study; researchers unraveled the underlying mechanism by showing that mouse fibroblasts lacking Neu1 proliferated; migrated and released large numbers of molecules that promoted the relentless expansion of connective tissue.
“The cells started acting more like cancer cells,” d’Azzo said. She previously reported evidence about the potential role of NEU1 deficiency in cancer; particularly sarcomas, which are cancers of the connective tissue. The researchers found that mouse fibroblasts lacking Neu1 release excessive numbers of molecules that degrade the extracellular matrix; as well as tiny vesicles (exosomes). The exosomes are loaded with factors that promote fibrosis; including the growth factor TGF-β and the signaling molecule WNT.
The extracellular matrix
Normal mouse and human fibroblasts cells are activate to proliferate and migrate when expose to exosomes containing TGF-β, WNT and relate molecules release by Neu1-deficient fibroblasts. Researchers check tissue from adults with idiopathic pulmonary fibrosis and find NEU1 production is significantly reduce (down-regulated) as compare to adults without the diagnosis. The investigators check an RNA sequencing database of 89 idiopathic pulmonary fibrosis patients and find NEU1 is among the most down-regulated of 66 genes include in the database.