Targeted metabolomic analyses of cellular models of pelizaeus-merzbacher disease reveal plasmalogen and myo-inositol solute carrier dysfunction

Lipids in Health and Disease

Research

Tara Smith¹  Dayan B Goodenowe¹  Paul L Wood¹  Lindsay Pelzer¹ 

[1] Phenomenome Discoveries Inc, 204-407 Downey Road, SK S7N 4L8, Saskatoon, Canada;

关键词: leukodystrophy;    Pelizaeus-Merzbacher disease;    fibroblasts;    lymphocytes;    158JP oligodendrocytes;    plasmalogens;    myo-inositol transporter;    peroxisomal disorders;   

DOI  :  10.1186/1476-511X-10-102

 received in 2011-05-16, accepted in 2011-06-17,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundLeukodystrophies are devastating diseases characterized by dys- and hypo-myelination. While there are a number of histological and imaging studies of these disorders, there are limited biochemical data available. We undertook targeted lipidomic analyses of Pelizaeus-Merzbacher disease (PMD) fibroblasts, PMD lymphocytes, and 158JP oligodendrocytes, a murine model of PMD, to define the lipid changes in these cell models. Further targeted metabolomics analyses were conducted to obtain a preliminary evaluation of the metabolic consequences of lipid changes and gene mutations in these cell models.ResultsIn both PMD fibroblasts and lymphocytes, and 158JP oligodendrocytes, ethanolamine plasmalogens were significantly decreased. Labeling studies with 158JP oligodendrocytes further demonstrated a decreased rate of lipid remodeling at sn-2. Targeted metabolomics analyses of these cells revealed dramatic increases in cellular levels of myo-inositol. Further uptake studies demonstrated increased rates of myo-inositol uptake by PMD lymphocytes.ConclusionsOur data demonstrating PlsEtn decrements, support previous studies indicating leukodystrophy cells possess significant peroxisomal deficits. Our data for the first time also demonstrate that decrements in peroxisomal function coupled with the PLP1 gene defects of PMD, result in changes in the function of membrane myo-inositol solute carriers resulting in dramatic increases in cellular myo-inositol levels.

【 授权许可】

CC BY   
© Wood et al; licensee BioMed Central Ltd. 2011