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(MEMPHIS, Tennessee – July 17, 2019) What is a family of rare hereditary diseases that can teach scientists about more common health problems such as fibrosis? Plenty, based on research conducted today by scientists from the St. Jude Children's Research Hospital in the newspaper Progress of science.
The researchers found an badociation between a neuraminidase 1 (NEU1) enzyme deficiency and connective tissue formation (fibrosis) in organs such as muscles, kidneys, liver, heart and lungs. Fibrosis includes potentially life-threatening conditions such as idiopathic pulmonary fibrosis.
Mutations in the NEU1 gene cause sialidosis, a lysosomal storage-related disease that belongs to a large group of pediatric-related diseases. "This is the first time that NEU1 is badociated with fibrotic conditions," said corresponding author Alessandra d'Azzo, Ph.D., member and director of the St. Jude Genetics Department. "NEU1 is an important enzyme that breaks down sugar-containing molecules in many cells of the body, but it has not really been taken into account by the health problems of adults.
"Based on these findings, it is interesting to think that the levels of NEU1 expression could help identify individuals at risk of fibrosis or to clarify their prognosis, particularly in the absence of Information on the cause or possible treatment, "she said. Fibrosis occurs when an excess of connective tissue is produced, accumulates and disrupts the normal functioning of the muscle, lungs, liver, heart and other tissues. The connective tissue is produced in part by fibroblast cells.
First evidence
The results are based on previous research from Azzo's laboratory. This work focused on mice lacking the Neu1 gene. The mice developed muscle atrophy when the connective tissue proliferated and invaded the muscle.
In this study, the researchers elucidated the underlying mechanism by showing that mouse fibroblasts lacking Neu1 proliferated, migrated, and released a large number of molecules that favored the relentless expansion of connective tissue. "The cells started to act more like cancer cells," said Azzo. She had previously reported evidence of the potential role of NEU1 deficiency in cancer, particularly sarcomas, which are connective tissue cancers.
The researchers found that mouse fibroblasts lacking Neu1 released an excessive number of extracellular matrix degrading molecules, as well as tiny vesicles (exosomes). Exosomes are responsible for factors that promote fibrosis, including TGF-β growth factor and the WNT signaling molecule. Normal human and mouse fibroblast cells were activated to proliferate and migrate when exposed to exosomes containing TGF-β, WNT, and related molecules released by Neu1-deficient fibroblasts.
Human disease
The researchers examined the tissues of adults with idiopathic pulmonary fibrosis and found that the production of NEU1 was significantly reduced (downregulated) compared to undiagnosed adults. The investigators checked an RNA sequencing database of 89 patients with idiopathic pulmonary fibrosis and found that NEU1 was one of the 66 most inhibited genes among those included in the database.
The research clearly highlights the NEU1 deficiency, badociated with catastrophic childhood disease, as a possible risk factor for the development and progression of fibrotic diseases in adults whose primary cause is unknown.
The findings also confirm Azzo's belief that extensive studies of rare pediatric diseases, such as lysosomal storage disorders, often help to explain the disease mechanisms underlying common disorders in the aging population.
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The first author is Diantha van de Vlekkert from Azzo's laboratory. The other authors are Yvan Campos, Eda Machado, Ida Annunziata, Huimin Hu, Elida Gomero and Xiaohui Qiu, of St. Jude; Jeroen Demmers from Erasmus University Medical Center, The Netherlands; Xinh-Xinh Nguyen and Carol Feghali-Bostwick of the South Carolina Medical University; and Antonella Bongiovanni from the Institute of Biomedicine and Molecular Immunology of Palermo, Italy.
The research was funded in part by grants from the National Institutes of Health (GM104981, DK095169, CA021764); the Assisi Foundation of Memphis; and ALSAC, St. Jude's fundraising and outreach organization.
St. Jude Media Contacts
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Michael Sheffield
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St. Jude Children's Research Hospital
The St. Jude Children's Research Hospital is a pioneer in understanding, treating and curing cancer in children and other life-threatening diseases around the world. It is the only cancer center designated by the National Cancer Institute and dedicated solely to children. The treatments developed at St. Jude have increased the overall childhood cancer survival rate from 20% to 80% since the opening of the hospital more than 50 years ago. St. Jude freely shares the advances he has made and every child saved at St. Jude means that doctors and scientists around the world can use this knowledge to save thousands of other children. Families never get a St. Jude bill for care, travel, accommodation and food, as the whole family should be concerned about helping their child to live. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.
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