Abstract
A deficiency of plasmalogens, caused by impaired peroxisomal metabolism affects normal development and multiple organs in adulthood. Treatment options aimed at restoring plasmalogen levels may be relevant for the therapy of peroxisomal and non-peroxisomal disorders. In this study we determined the in vivo efficacy of an alkyl glycerol (AG), namely, 1-O-octadecyl-rac-glycerol, as a therapeutic agent for defects in plasmalogen synthesis. To achieve this, Pex7 knockout mice, a mouse model for Rhizomelic Chondrodysplasia Punctata type 1 characterized by the absence of plasmalogens, and WT mice were fed a control diet or a diet containing 2% alkyl-glycerol. Plasmalogen levels were measured in target organs and the biochemical data were correlated with the histological analysis of affected organs. Plasmalogen levels in all peripheral tissues of Pex7 KO mice fed the AG diet for 2 months normalized to the levels of AG fed WT mice. In nervous tissues of Pex7 KO mice fed the AG-diet, plasmalogen levels were significantly increased compared to control fed KO mice. Histological analysis of target organs revealed that the AG-diet was able to stop the progression of the pathology in testis, adipose tissue and the Harderian gland. Interestingly, the latter tissues are characterized by the presence of lipid droplets which were absent or reduced in size and number when ether-phospholipids are lacking, but which can be restored with the AAG treatment. Furthermore, nerve conduction in peripheral nerves was improved. When given prior to the occurrence of major pathological changes, the AG-diet prevented or ameliorated the pathology observed in Pex7 KO mice depending on the degree of plasmalogen restoration. This study provides evidence of the beneficial effects of treating a plasmalogen deficiency with alkyl-glycerol.
Highlights
Ether-phospholipids are major constituents of cellular membranes and are characterized by an ether-bond at the sn-1 position of the glycerol backbone
In the peripheral nervous system (PNS), measurement of plasmalogens in sciatic nerves revealed that in Pex7 KO fed the alkyl glycerol (AG) diet plasmalogen levels increased to 2.3% of WT levels (Table 1)
Plasmalogen levels in spinal cord and cerebellum of treated Pex7 KO mice were higher than after the 2 month treatment period, displaying 2.9% of WT levels. These results indicate that AG can be used to increase plasmalogen levels in vivo and that different treatment periods should be considered depending if the target is systemic or nervous tissue
Summary
Ether-phospholipids are major constituents of cellular membranes and are characterized by an ether-bond at the sn-1 position of the glycerol backbone. Ether-phospholipids are divided into two groups, the distinctive feature being the presence of either a 1-O-alkyl or 1-0alkenyl side-chain at sn-1. Plasmalogens represent the etherphospholipids with a vinyl-ether linkage (alkenylacyl-glycerophospholipids) whereas platelet-activating factor (PAF) is a typical example of the ether-phospholipids with an 1-O-alkyl ether linkage (alkylacyl-glycerophospholipids) [1,2]. The biosynthetic pathway of ether-phospholipids, involves several enzymatic steps performed in peroxisomes and the endoplasmatic reticulum [3,4]. A genetic deficiency affecting either the biogenesis of peroxisomes or one of the two peroxisomal enzymes, i.e. glyceronephosphate O-acyltransferase (Gnpat) and alkylglycerone phosphate synthase (Agps) involved in ether-phospholipid biosynthesis, leads to absent or reduced levels of ether-phospholipids [5,6,7,8]. The distribution and composition of plasmalogens varies between different tissues with brain, kidney and testes having relatively high levels of plasmalogens
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