Activation of mammalian terget of rapamycin kinase and glycogen synthase kinase-3β accompanies abnormal accumulation of cholesterol in fibroblasts from Niemann-Pick type C patients.

Abstract

Niemann Pick type C (NPC) lysosomal disorder is linked to the disruption of cholesterol transport. Recent data suggest that the molecular background of this disease is more complex. It was found that accumulation of cholesterol and glycolipids in the late endosomal/lysosomal compartment of NPC1 cells may affect mitochondrial functions. In this study, primary skin fibroblasts derived from skin biopsies of two anonymous patients with NPC-carrying mutations in the NPC1 gene, characterized by a high total cholesterol content, as well as two healthy donors were used. The presence of signaling proteins in the whole cell lysates and mitochondrial fractions were examined by Western blotting assay. In this report, we provide experimental evidence that in NPC1 cells, dysfunction of mitochondria and cellular metabolism, as reported by Wos et al in 2016, coexist with alterations in signal transduction pathways, such as the mammalian target of rapamycin, AKT, phosphoinositide-dependent protein kinase-1, glycogen synthase kinase-3β, and Jun amino-terminal kinase, leading to abnormal cholesterol accumulation and distribution. Differences in signal transduction between control and NPC1 cells may suggest that the latter cells experienced significant alterations in the complex molecular mechanisms that control cellular energy metabolism and vesicular transport.