From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

Abstract

The emerging diverse roles of ether (phospho)lipids in nervous system development and function in health and disease are currently attracting growing interest. Plasmalogens, a subgroup of ether lipids, are important membrane components involved in vesicle fusion and membrane raft composition. They store polyunsaturated fatty acids and may serve as antioxidants. Ether lipid metabolites act as precursors for the formation of glycosyl-phosphatidyl-inositol anchors; others, like platelet-activating factor, are implicated in signaling functions. Consolidating the available information, we attempt to provide molecular explanations for the dramatic neurological phenotype in ether lipid-deficient human patients and mice by linking individual functional properties of ether lipids with pathological features. Furthermore, recent publications have identified altered ether lipid levels in the context of many acquired neurological disorders including Alzheimer's disease (AD) and autism. Finally, current efforts to restore ether lipids in peroxisomal disorders as well as AD are critically reviewed.

Unequivocal mapping of molecular ether lipid species by LC-MS/MS in plasmalogen-deficient mice

“…Furthermore, ether lipid deficiency is thought to be the main cause of the phenotype of rhizomelic chondrodysplasia punctata and the respective features of Zellweger spectrum disorders 15 ,3 . Still, the functional role of the vinyl ether double bond remains elusive 16 . Also, it has not been studied in detail whether plasmalogen depletion -reported in some neurodegenerative diseases 6 -is accompanied by changes in 1-O-alkyl lipids in a parallel or opposing manner 16 As demonstrated in Figure 2 and Figure 3, 1-O-alkyl and 1-O-alk-1'-enyl lipids cannot be readily discriminated purely on the basis of exact mass and MS/MS fragment spectra.…”

“…Still, the functional role of the vinyl ether double bond remains elusive 16 . Also, it has not been studied in detail whether plasmalogen depletion -reported in some neurodegenerative diseases 6 -is accompanied by changes in 1-O-alkyl lipids in a parallel or opposing manner 16 As demonstrated in Figure 2 and Figure 3, 1-O-alkyl and 1-O-alk-1'-enyl lipids cannot be readily discriminated purely on the basis of exact mass and MS/MS fragment spectra. While ESI in positive mode only provides strongly limited side chain information, the here used negative mode gives specific details about the sn-1 and sn-2 residues.…”

Plasmalogen deficiency and neuropathology in Alzheimer's disease: Causation or coincidence?

“…Severe neurological diseases caused by plasmalogen deficiency such as RCDP is analogous situation that demonstrate neurodegenerative effects of plasmalogen deficiency. Myelination deficits, enlarged ventricles, and subarachnoidal spaces, and cerebellar atrophy are the main neurological abnormalities described in RCDP [65]. Cerebellar atrophy is considered to be due to loss of Purkinje cells [65].…”

“…Myelination deficits, enlarged ventricles, and subarachnoidal spaces, and cerebellar atrophy are the main neurological abnormalities described in RCDP [65]. Cerebellar atrophy is considered to be due to loss of Purkinje cells [65]. Therefore, plasmalogen deficiency appears to meet Bradford Hill criteria for causal association with neurodegeneration to a considerable extent, but not for AD causation.…”

Introducing a new column, Peer Review accreditation, and a Focus On… Plasmalogens

“…Indicatively, the biophysical properties of plasmalogens and the regulation of their biosynthesis in bacteria and mammals are reviewed . Moreover, plasmalogen functions, for example, in peroxisome biogenesis and neuronal development, and pathogenic roles are discussed .…”