Role of cystathionine-β-synthase and hydrogen sulfide in down syndrome.

Down syndrome (DS) is a genetic condition where the person affected by it is born with an additional - full or partial - copy of chromosome 21. DS presents with characteristic morphological features and is associated with a wide range of biochemical alterations and maladaptations. Cystathionine-β-synthase (CBS) - one of the key mammalian enzymes responsible for the biogenesis of the gaseous transmitter hydrogen sulfide (H2S) - is located on chromosome 21, and people with DS exhibit a significant upregulation of this enzyme in their brain and other organs. Even though 3-mercaptopyruvate sulfurtransferase - another key mammalian enzyme responsible for the biogenesis of H2S and of reactive polysulfides - is not located on chromosome 21, there is also evidence for the upregulation of this enzyme in DS cells. The hypothesis that excess H2S in DS impairs mitochondrial function and cellular bioenergetics was first proposed in the 1990s and has been substantiated and expanded upon over the past 25 years. DS cells are in a state of metabolic suppression due to H2S-induced, reversible inhibition of mitochondrial Complex IV activity. The impairment of aerobic ATP generation in DS cells is partially compensated by an upregulation of glycolysis. The DS-associated metabolic impairment can be reversed by pharmacological CBS inhibition or CBS silencing. In rodent models of DS, CBS upregulation and H2S overproduction contribute to the development of cognitive dysfunction, alter brain electrical activity, and promote reactive gliosis: pharmacological inhibition or genetic correction of CBS overactivation reverses these alterations. CBS can be considered a preclinically validated drug target for the experimental therapy of DS.