Brain Advance Access published online on November 20, 2008
Brain, doi:10.1093/brain/awn295
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Plasmalogens participate in very-long-chain fatty acid-induced pathology
Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Correspondence to:
Pedro Brites, Academic Medical Center, Lab GMZ F0-224, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands E-mail: p.m.brites{at}amc.uva.nl
Peroxisomes are organelles responsible for multiple metabolic pathways including, the biosynthesis of plasmalogens, a class of phospholipids, and the β-oxidation of very-long-chain fatty acids (VLCFA). Lack of peroxisomes or dysfunction in any of their normal functions is the cellular basis for human peroxisomal disorders. Here we used mouse models to understand and define the biochemical and cellular determinants that mediate the pathophysiological consequences caused by peroxisomal dysfunctions. We investigated the role and effects of cellular plasmalogens and VLCFA accumulation in liver, testis and nervous tissue using Pex7 and Abcd1 knockout (KO) mice. In addition, we also generated a Pex7:Abcd1 double KO mouse to investigate how different peroxisomal dysfunctions modulate cellular function and pathology. We found that plasmalogens function as fundamental structural phospholipids and protect cells from damage caused by VLCFA accumulation. In testis, plasmalogens protect spermatocytes from VLCFA-induced degeneration and apoptosis. In nervous tissue, we found that gliosis, inflammatory demyelination and axonopathy caused by accumulation of VLCFA are modulated by plasmalogens. Our findings demonstrate the importance of normal peroxisomal functioning and allow the understanding of the pathological causality of peroxisomal dysfunctions. Nervous tissue deficient in plasmalogens is more prone to damage, illustrating the importance of plasmalogens in peroxisomal disorders including Zellweger syndrome and X-linked adrenoleukodystrophy.
Key Words: peroxisome; plasmalogen; very-long-chain fatty acids; demyelination; neuropathy
Abbreviations: C26:0, hexacosanoic acid; CMAP, compound muscle action potentials; DKO, double knockout; KO, knockout; MNCV, motor nerve conductance velocity; VLCFA, very-long-chain-fatty acids; WT, wild type; X-ALD, X-linked adrenoleukodystrophy
Received July 10, 2008. Revised October 8, 2008. Accepted October 10, 2008.