In vitro and in vivo plasmalogen replacement evaluations in rhizomelic chrondrodysplasia punctata and Pelizaeus-Merzbacher disease using PPI-1011, an ether lipid plasmalogen precursor

Lipids in Health and Disease

Research

Paul L Wood¹  Nancy E Braverman²  Wei Cui²  Greg Ehrmantraut³  Wei Jin³  M Amin Khan³  Tara Smith³  Dayan B Goodenowe³ 

[1] Dept. of Pharmacology, DeBusk College of Osteopathic Medicine, Lincoln Memorial University, 6965 Cumberland Gap Parkway, 37752, Harrogate, TN, USA;Depts. of Human Genetics and Pediatrics, McGill University-Montreal Children's Hospital Research Institute, 4060 Ste-Catherine West, PT-406.2, H3Z 2Z3, Montreal, QC, Canada;R&D Dept., Phenomenome Discoveries Inc, 204-407 Downey Road, S7N 4L8, Saskatoon, SK, Canada;

关键词: Rhizomelic chrondrodysplasia punctata type 1;    Rhizomelic chrondrodysplasia punctata type 2;    Pelizaeus-Merzbacher disease;    Pex7 mouse;    lymphocytes;    plasmalogen precursor;    DHA;    peroxisomal disorders;    PPI-1011;   

DOI  :  10.1186/1476-511X-10-182

 received in 2011-08-09, accepted in 2011-10-18,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundChildhood peroxisomal disorders and leukodystrophies are devastating diseases characterized by dysfunctional lipid metabolism. Plasmalogens (ether glycerophosphoethanolamine lipids) are decreased in these genetic disorders. The biosynthesis of plasmalogens is initiated in peroxisomes but completed in the endoplasmic reticulum. We therefore undertook a study to evaluate the ability of a 3-substituted, 1-alkyl, 2-acyl glyceryl ether lipid (PPI-1011) to replace plasmalogens in rhizomelic chrondrodysplasia punctata type 1 (RCDP1) and rhizomelic chrondrodysplasia punctata type 2 (RCDP2) lymphocytes which possess peroxisomal mutations culminating in deficient plasmalogen synthesis. We also examined plasmalogen synthesis in Pelizaeus-Merzbacher disease (PMD) lymphocytes which possess a proteolipid protein-1 (PLP1) missense mutation that results in abnormal PLP1 folding and it's accumulation in the endoplasmic reticulum (ER), the cellular site of the last steps in plasmalogen synthesis. In vivo incorporation of plasmalogen precursor into tissue plasmalogens was also evaluated in the Pex7 mouse model of plasmalogen deficiency.ResultsIn both RCDP1 and RCDP2 lymphocytes, PPI-1011 repleted the target ethanolamine plasmalogen (PlsEtn16:0/22:6) in a concentration dependent manner. In addition, deacylation/reacylation reactions resulted in repletion of PlsEtn 16:0/20:4 in both RCDP1 and RCDP2 lymphocytes, repletion of PlsEtn 16:0/18:1 and PlsEtn 16:0/18:2 in RCDP2 lymphocytes, and partial repletion of PlsEtn 16:0/18:1 and PlsEtn 16:0/18:2 in RCDP1 lymphocytes. In the Pex7 mouse, oral dosing of labeled PPI-1011 demonstrated repletion of tissue levels of the target plasmalogen PlsEtn 16:0/22:6 with phospholipid remodeling also resulting in significant repletion of PlsEtn 16:0/20:4 and PlsEtn 16:0/18:1. Metabolic conversion of PPI-1011 to the target plasmalogen was most active in the liver.ConclusionsOur data demonstrate that PPI-1011 is activated (removal of 3-substitution) and converted to PlsEtn in vitro in both RCDP1 and RCDP2 lymphocytes and in vivo in the Pex7 mouse model of RCPD1 effectively bypassing the peroxisomal dysfunction present in these disorders. While PPI-1011 was shown to replete PlsEtns 16:0/x, ether lipid precursors of PlsEtn 18:0/x and PlsEtn 18:1/x may also be needed to achieve optimal clinical benefits of plasmalogen replacement in these complex patient populations. In contrast, only limited plasmalogen replacement was observed in PMD lymphocytes suggesting that the effects of protein misfolding and accumulation in the ER negatively affect processing of plasmalogen precursors in this cellular compartment.

【 授权许可】

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