Changes in macrophage morphology in a Gaucher disease model are dependent on CTP:phosphocholine cytidylyltransferase alpha.
We have recently shown that phosphatidylcholine (PC) metabolism is altered in a macrophage model of Gaucher disease. We now demonstrate that treatment of macrophages with conduritol-B-epoxide (CBE), a glucocerebrosidase inhibitor, results in elevated activity of CTP:phosphocholine cytidylyltransferase (CCT), the rate-limiting enzyme in the pathway of PC biosynthesis. Furthermore, we provide evidence for a role for CCT in Gaucher macrophage growth by using macrophages derived from a genetically modified mouse which lacks a specific CCT isoform, CCTalpha, in macrophages. Upon CBE-treatment, macrophage size, analyzed by microscopy and by FACS, was significantly increased in macrophages from control mice, but did not increase, or increased to a much lower extent, in CCTalpha-/- macrophages. Together, these results suggest that the increase in PC biosynthesis is mediated via CCTalpha, and suggests a possible role for macrophage CCTalpha in Gaucher disease pathology.
Kacher
Yaacov
Y
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Golan
Avner
A
Pewzner-Jung
Yael
Y
Futerman
Anthony H
AH
D000818:Animals; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D019916:Choline-Phosphate Cytidylyltransferase / Q000096:biosynthesis* / Q000172:deficiency; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005776:Gaucher Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D010713:Phosphatidylcholines; D007294:Inositol; D019916:Choline-Phosphate Cytidylyltransferase; C500611:Pcyt1a protein, mouse; D005962:Glucosylceramidase; C011423:conduritol epoxide