Abstract
Inherited deficiency in ether lipids, a subgroup of phospholipids whose biosynthesis needs peroxisomes, causes the fatal human disorder rhizomelic chondrodysplasia punctata. The exact roles of ether lipids in the mammalian organism and, therefore, the molecular mechanisms underlying the disease are still largely enigmatic. Here, we used glyceronephosphate O‐acyltransferase knockout (Gnpat KO) mice to study the consequences of complete inactivation of ether lipid biosynthesis and documented substantial deficits in motor performance and muscle strength of these mice. We hypothesized that, probably in addition to previously described cerebellar abnormalities and myelination defects in the peripheral nervous system, an impairment of neuromuscular transmission contributes to the compromised motor abilities. Structurally, a morphologic examination of the neuromuscular junction (NMJ) in diaphragm muscle at different developmental stages revealed aberrant axonal branching and a strongly increased area of nerve innervation in Gnpat KO mice. Post‐synaptically, acetylcholine receptor (AChR) clusters colocalized with nerve terminals within a widened endplate zone. In addition, we detected atypical AChR clustering, as indicated by decreased size and number of clusters following stimulation with agrin, in vitro. The turnover of AChRs was unaffected in ether lipid‐deficient mice. Electrophysiological evaluation of the adult diaphragm indicated that although evoked potentials were unaltered in Gnpat KO mice, ether lipid deficiency leads to fewer spontaneous synaptic vesicle fusion events but, conversely, an increased post‐synaptic response to spontaneous vesicle exocytosis. We conclude from our findings that ether lipids are essential for proper development and function of the NMJ and may, therefore, contribute to motor performance. Read the Editorial Highlight for this article on page 463.
Highlights
Electrophysiological abnormalities are observed at ether lipid-deficient neuromuscular junction (NMJ) Based on the morphological abnormalities that we observed in NMJs of Gnpat KO mice, we evaluated functional consequences by recording neuromuscular transmission in phrenic nerve-diaphragm explants dissected from adult WT and Gnpat KO mice
Given the numerous signal transduction processes involved in NMJ maturation, lipid rafts are probable candidates contributing to the observed alterations in Gnpat-deficient mice, as these small membrane domains serve as organizing platforms for signaling events (Simons and Toomre 2000)
In lipid raft fractions isolated from Chinese hamster ovary (CHO) cells with a deficiency in either alkyldihydroxyacetone phosphate synthase, catalyzing the second step in ether lipid biosynthesis (Fig. 1), or peroxisome biogenesis, detergent resistance and lipid composition were normal (Honsho et al 2008)
Summary
Plasmalogens have been described to be enriched in lipid rafts ( termed membrane rafts) (Pike et al 2002), small heterogeneous membrane domains, which are highly dynamic and compartmentalize cellular processes like signal transduction (Simons and Ikonen 1997; Pike 2006) This still expanding range of functions is reflected by the multifaceted pathogenesis of RCDP and other peroxisomal disorders, but alterations in the levels of ether lipids have been reported in more common disease conditions (Berger et al 2016), including Alzheimer’s disease (Kou et al 2011; Goodenowe et al 2007), Parkinson’s disease (Fabelo et al 2011), Down syndrome (Murphy et al 2000), or hypertension (Graessler et al 2009)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
