Columbia University Medical Center (CUMC) researchers have discovered that a lack of the enzyme prohormone covertase (PC1) in the brain is connected to most of the neuro-hormonal abnormalities in Prader-Willi syndrome, a hereditary condition that causes extreme hunger and severe obesity from childhood. The discovery provides insight into the molecular systems underlying the syndrome and highlights a novel focus on for drug therapy.
The particular findings were published online in the Diary of Clinical Investigation .
“While we now have known for some time which genes are implicated in Prader-Willi syndrome, it has not been clear how those variations actually trigger the disease, ” said lead author Mack C. Burnett, PhD, a post-doctoral research scientist within pediatrics at CUMC. “Now that we have found a key hyperlink between these mutations and the syndrome’s major hormonal functions, we can begin to search for new, more precisely targeted remedies. ”
An estimated one in 15, 1000 people have Prader-Willi syndrome (PWS). The syndrome is brought on by abnormalities in a small region of chromosome 15, which leads in order to dysfunction in the hypothalamus — which contains cells that will regulate hunger and satiety — and other regions of the mind. A defining characteristic of PWS is insatiable food cravings. People with PWS typically have extreme obesity, reduced growth hormone plus insulin levels, excessive levels of ghrelin (a hormone that creates hunger), and developmental disabilities. There is no cure and couple of effective treatments for PWS.
Dr . Burnett and her colleagues used stem cell techniques to transform skin cells from PWS patients and unaffected regulates into brain cells. Analysis of the stem cell-derived neurons revealed significantly reduced levels of PC1 in the patients’ tissue, compared to the controls. The cells from PWS patients also acquired abnormally low levels of a protein, NHLH2, which is manufactured by NHLH2, a gene that also helps to produce PC1.
To confirm whether PC1 deficiency plays a role in PWS, the particular researchers examined transgenic mice that do not express Snord116, a gene that is deleted in the region of chromosome 15 which is associated with PWS. The mice were found to be lacking in NHLH2 and PC1 and displayed most of the hormone-related abnormalities seen in PWS, according to study leader Rudolph D. Leibel, MD, professor of pediatrics and medicine plus co-director of the Naomi Berrie Diabetes Center at CUMC.
“The findings strongly suggest that PC1 is an excellent therapeutic target for PWS, ” said Dr . Burnett. “There doesn’t seem to be anything wrong with the gene which makes PC1 — it’s just not getting activated properly. Whenever we could elevate levels of PC1 using drugs, we might have the ability to alleviate some of the symptoms of the syndrome. ”
“This is an outstanding example how research on individual stem cells can lead to novel insight into a disease and provide the platform for the testing of new therapies, ” said He or she Egli, PhD, a stem cell scientist who is a good assistant professor of developmental cell biology (in Pediatrics) and a senior author on the paper.
“This study changes how we think about this devastating disorder, ” stated Theresa Strong, PhD, chair of the scientific advisory panel of the Foundation for Prader-Willi Research and the mother of the child with PWS. “The symptoms of PWS have been very puzzling and hard to reconcile. Now that we have an explanation for the wide range of symptoms, we can move forward with developing a drug that will addresses their underlying cause, instead of treating each sign individually. ”
Following the findings reported on this paper, the Columbia research team began collaborating along with Levo Therapeutics, a PWS-focused biotechnology company, to convert the current research into therapeutics.
Materials provided by Columbia University Medical Center . Note: Content may be edited for design and length.