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Ether lipids and their elusive function in the nervous system: a role for plasmalogens

2017; Wiley; Volume: 143; Issue: 5 Linguagem: Inglês

10.1111/jnc.14156

1471-4159

Eric J. Murphy,

Neuroscience and Neuropharmacology Research

In this editorial, we highlight the recent work of Dorninger et al. that demonstrates a reduction in plasmalogens in the motor end plate is associated with a reduction in motor end plate function. This reduction in function is illuminated in reduced muscle function in these mice, corresponding with the reduction in acetylcholine release and in its receptor density observed in these mice. Ether lipids, specifically, plasmalogens, are special phospholipids. This is something that was highly stressed during my graduate training in Professor Lloyd Horrocks’ laboratory at The Ohio State University. He passed on to me a passion for a phospholipid that is special and esoteric, so much so that their biological functional significance is still one of much speculation. Plasmalogens are specialized phospholipids that are enriched in the central nervous system, comprising approximately 23% of all brain phospholipids (Panganamala et al. 1971), and contain either a choline or an ethanolamine as the head group. Unlike most phospholipids that have an ester bond at the sn-1 linkage, a plasmalogen has an ether bond at the sn-1 position and there is a desaturation between the α and β carbon, making what is called a vinyl ether linkage. Because the sn-2 position of plasmalogens are a reservoir of arachidonic acid (Panganamala et al. 1971; Gross 1984; Farooqui et al. 1995), the speculation regarding their potential role in lipid-mediated signaling is merely magnified (Fig. 1). My mentor proposed that plasmalogens are a putative signaling molecule in the brain (Horrocks et al. 1986a,b; Farooqui et al. 1995). This is not without precedence, as in the heart there is a specialized phospholipase A2 that hydrolyzes the arachidonic acid from the sn-2 position (Ford et al. 1991), which facilitates IL-1β and thrombin receptor stimulation releasing arachidonic acid in the heart (McHowat and Liu 1997; McHowat and Creer 2000). Similar to hypoxia-induced reduction in plasmalogens in myocytes (Ford and Gross 1989; McHowat et al. 1998), in the CNS plasmalogens are reduced following a number of different injury mechanisms (Saunders et al. 1987; Murphy et al. 1994). Although the mechanisms underlying this injury-induced reduction in nervous system plasmalogens remains elusive as does a direct receptor-mediated signal transduction, a specialized phospholipase A2 has been isolated in the brain that hydrolyzes the sn-2 position of plasmalogens (Bock 1989; Hirashima et al. 1992). However, consistent with the use of plasmalogens as a key component of lipid-mediated signal transduction, we have also demonstrated a rapid turnover of choline plasmalogen in the brain, with the gray matter pool having a half-life between 7–15 min (Rosenberger et al. 2002). Further, plasmalogens also form secondary, very bioactive lipid second messengers (Tigyi 2001) that may augment a plasmalogen-mediated signaling cascade thereby impacting their putative role in signaling in the brain and downstream brain function. We have demonstrated that like in heart (Murphy et al. 2004), fatty acid binding protein-3 (FABP3) is involved in plasmalogen biosynthesis in the brain (Murphy et al. 2005). Previous work demonstrated that FABP1 expression enhances plasmalogen levels (Murphy et al. 2000), but the mechanism underlying this increase is unknown. However, it is important because in the brain, ethanolamine plasmalogen is significantly reduced in Alzheimer disease (AD) (Han et al. 2001) and in aged rat brain (André et al. 2005), which could be linked to the reported reduction in FABP3 in brain regions affected by AD (Cheon et al. 2003) and in aged mice (Pu et al. 1999). Again, this is a critical observation suggesting that plasmalogens have a role in the aged brain and in the pathophysiology of AD, but the exact mechanisms underlying their function are elusive and open to speculation. Additional potential roles for plasmalogen are a role in membrane trafficking and fusion events (Glaser and Gross 1994; Thai et al. 2001) and as molecules that scavenge free radicals (Zoeller et al. 1988; Nagan and Zoeller 2001). While a role for scavenging free radical may be consistent with the reduction in plasmalogens in spinal cord injury where free radical-mediated damage occurs (Saunders et al. 1987; Murphy et al. 1994), the overall idea that scavenging free radicals in the brain is the primary function of plasmalogens remains poorly supported in vivo. However, the concept that plasmalogens are important in vesicle fusion events is supported by a recent paper by Dorninger et al. as this group sheds considerable light on the role for plasmalogens in the nervous system specifically at the neuromuscular junction. Using the glyceronephosphate-O-acyltransferase (Gnpat) knockout that encodes dihydroxyacetone phosphate O-acyltransferase (DHAPAT), the enzyme that catalyzes the first step in ether lipid biosynthesis in the peroxisome, they examined the impact of the complete absence of plasmalogens at the level of the neuromuscular junction (Dorninger et al. 2017). It is known that these mice, a model for rhizomelic chondrodysplasia punctata, have motor deficits and reduced muscle strength, which was further characterized by a reduction in numerous measures of motor function. Interestingly, there is a net increase in motor end plate area, suggesting a disconnect between the motor end plate area and motor function. However, when they examined acetylcholine receptor (AChR) clustering, they note a reduction in the number of AChR clusters and a reduced area of these clusters. Although the number and size of the AChR clusters is reduced, the half-life of the receptor is not altered, suggesting that the major impact is a potential disruption in AChR function. Nonetheless, upon stimulation, there is a nearly 50% reduction in quantal release, consistent with a marked reduction in motor end plate function. The alteration in motor function and strength are consistent with a reduction in the size of the myotube, again suggesting a derangement of motor end plate structure and function in the absence of plasmalogens. These findings add a new, but important twist to the potential role for plasmalogens and ether lipids in the nervous system. Further, the absence of plasmalogens and the functions demonstrated herein by Dorninger et al. (2017) are more consistent with a structural change that results in reduced function, which is consistent with the observed importance of plasmalogens in vesicle fusion events rather than a direct impact in generating second messengers via involvement in lipid-mediated signaling. It has been nearly 32 years since my love affair with plasmalogens started, and it appears the story is as complicated as ever. Yet what remains is that these molecules may simply have a multi-faceted role in nervous system function spanning multiple mechanisms, from a structural importance to direct involvement in lipid-mediated signal transduction. I am forever indebted to my mentor Lloyd A. Horrocks for imparting a love of lipids in my life, including that of ether lipids, specifically plasmalogen, in the CNS. Further, and as always, I thank Cindy Murphy for typed preparation of this manuscript. E.J. Murphy is an editor with the Journal of Neurochemisty.