Depressing Ceramide

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Science  25 Apr 2008:
Vol. 320, Issue 5875, pp. 426
DOI: 10.1126/science.320.5875.426b

Cystic fibrosis, a genetic disease associated with frequent lung infections and a shortened life span, is caused by a defect in the CFTR gene, which encodes a membrane transporter. Although it is not clear exactly how defective CFTR links to the symptoms, the mutant protein is known to increase the pH in intracellular organelles. On the basis of results obtained from patients' cells and from mice carrying mutated Cftr (which produces a cystic fibrosis-like disease), Teichgräber et al. suggest that this rise in pH increases susceptibility to lung infection by altering levels of ceramide, a membrane constituent that can also trigger cell death. The higher pH inhibits the enzyme that breaks down ceramide, and the resulting excess of ceramide increases vulnerability to lung infection. Blocking the biosynthesis of ceramide via acid sphingomyelinase normalizes ceramide levels and, most tellingly, renders the Cftr-deficient mice resistant to lung infections. This block can be achieved with amitriptyline (Elavil), a drug approved for treatment of depression. Normalization of ceramide levels in the lungs of patients with cystic fibrosis may be a promising therapeutic approach. — KK

Nat. Med. 14, 382 (2008).

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