PEROXISOMAL DISEASE CELL-LINES WITH CELLULAR PLASMALOGEN DEFICIENCY HAVE IMPAIRED MUSCARINIC CHOLINERGIC SIGNAL-TRANSDUCTION ACTIVITY AND AMYLOID PRECURSOR PROTEIN SECRETION

We tested whether alterations in membrane lipid composition associated with peroxisomal diseases affect muscarinic cholinergic signal transd uction activity and amyloid precursor protein (APP) secretion in cultu red human skin fibroblasts and Chinese hamster ovary (CHO) mutants. We found that in cell lines from patients with peroxisomal disorders whe re plasmalogen levels were low, the low-Km GTPase activity was not ind uced by carbachol, and APP secretion was reduced. This effect on signa l transduction activity was not associated with decreased levels of th e M1-muscarinic cholinergic receptor or its associated heterotrimeric G-protein. Specifically, this decrease was associated with a plasmalog en deficiency since a CHO cell line with only a deficit in plasmalogen s was as severely affected as were generalized peroxisomal disorder ce ll lines, Thus, plasmalogens appear to be implicated in muscarinic cho linergic signal transduction and secretion of APP. These results provi de new insights about the pathophysiology of peroxisomal diseases and may be relevant to Alzheimer's disease where reduced plasmalogen level s have been reported. (C) 1998 Academic Press.