A team of researchers at the University of Fribourg has found evidence for a mechanism that contributes to the impaired metabolism of individuals with Down syndrome. Their organism seems poisoned by an excess of hydrogen sulfide, caused by a gene on chromosome 21. This result offers an opening towards a medical treatment for some of Down syndrome’s main effects.

The team has studied live human cells, to understand a mechanism that causes cell dysfunction in Down syndrome (trisomy). They showed how cells are poisoned by an excess of the biological gas hydrogen sulfide (H₂S).  «What we did is study human cells with and without Down syndrome, from the point of view of H₂S poisoning.» Explains team leader Professor Csaba Szabo.  «We showed that the Down cells have high levels of H₂S, high levels of the protein involved in the production of H₂S coded for on Chromosome 21, and that this impaired energy production in cells.» Most importantly, the researchers also found that when they suppressed the production of H₂S, the impaired cells recovered their full capacity to produce energy.  «If we extrapolate this to neurons, we can hope that inhibiting some of the extra production of H₂S might improve neuronal and cognitive function in Down syndrome»

Cells poisoned by hydrogen sulfide
The idea behind the new research results was first put forward in 2003 by the French researcher Pierre Kamoun. A highly respected specialist in Down syndrome research, Professor Kamoun, hypothesized that cells were poisoned by an excess of hydrogen sulfide throughout the body.

«The cells of individuals with Down syndrome contain far too much H₂S» says Professor Szabo. «You could say they are swimming in a poisonous gas.» This impairs cell function by severely harming the mitochondria, the tiny organelles that provide the energy in all our cells.

Why did it take so long to test Prof. Kamoun’s hypothesis? At the time, the role of hydrogen sulfide as a gaseous transmitter in the body was little known.  Professor Szabo explains: «But the field of H₂S biology has matured a lot since then, in part due to our group’s work, so that it is no longer a heresy to suggest that H₂S has a regulatory role in our cells.» There were also technical improvements: it is now possible to study the molecular working of cells without breaking them, which has helped a lot. The team at Unifr was able to observe the expression of the enzyme, the production of sulfide and its effect on the cell in living human cells in their lab.

Treatments for Down syndrome
The result opens a new avenue towards a treatment for some of the main effects of Down syndrome. Based on the newly published article, researchers can now design and perform clinical trials that could reduce the production of H₂S. They already know the pathways for the production of H₂S, in particular the enzyme coded on Chromosome 21, and how to inhibit its action.

«But we have to remain very cautious» points out Professor Szabo. «Many people have previously discovered things that might work for Down syndrome, and then everybody was disappointed to find out that it did not lead to treatments.»

At present there is no treatment and the affected individuals are supported with special care. But treatment is not impossible. While ‘curing’ the condition by inactivating the third copy of Chromosome 21 in every cell is not feasible with current technology, the effect of the extra copy can be mitigated. That would offer the perspective of a tremendous improvement in the lives of the affected people.

Down syndrome occurs in about one birth in a thousand, and is the most prevalent genetic condition in humans, affecting more than 5 million people worldwide.

The results are published in the latest issue of the Proceedings of the National Academy of Sciences (PNAS, September 2019). The authors are Theodora Panagaki, Elisa Randi, Fiona Augsburger and Csaba Szabo. Title: Overproduction of H₂S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome.  The research is supported by the Swiss National Science Foundation and the Lejeune Foundation (Paris).