Involvement of caspase-3 and GD3 ganglioside in ceramide-induced apoptosisin Farber disease

Farber's disease (FD) is a rare genetic disorder caused by ceramidase defic iency, which results in ceramide accumulation in lung, liver, colon, skelet al muscle, cartilage, and bone. Although this disease has been symptomatica lly characterized, little is known about its molecular pathogenetic process . Because recent studies reported that ceramide accumulation induces GD3 ga nglioside formation and apoptosis, we investigated, in tissue obtained via colonoscopy from seriously involved patients, the possible involvement of c eramide in FD colonocyte destruction. Histochemical and TUNEL analyses of p araffin-embedded sections revealed that 45 +/- 4.3% of FD colonocytes showe d morphological signs of apoptosis compared with the 8 +/- 2.3% of constitu tive epithelial cell death. Importantly, immunohistochemical study for pro- apoptotic factors showed that GD3 accumulation colocalized with active casp ase-3 and cleaved K18 in FD colon tissue. These findings provide evidence f or a role of the apoptotic ceramide pathway in the pathogenesis of FD.