title: Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture.
abstract: Saturated very long chain fatty acids (VLCFAs; > or =C22:0) accumulate in X-linked adrenoleukodystrophy (X-ALD, OMIM 300100), a severe hereditary neurodegenerative disease, due to peroxisomal impairment. Previous studies analysed the development of X-ALD in humans and gene knockout animal models. However, the toxic effect of VLCFA leading to severe symptoms with progressive and multifocal demyelination, adrenal insufficiency and inflammation still remains unclear. To understand the toxic effects of VLCFA in the brain, here we exposed neural cells to VLCFA and analysed the cellular consequences. We found that oligodendrocytes and astrocytes challenged with docosanoic- (C22:0), tetracosanoic- (C24:0) and hexacosanoic acids (C24:0) die within 24 h. VLCFA-induced depolarization of mitochondria in situ and increased intracellular Ca2+ level in all three brain cell types provides indications about the mechanism of toxicity of VLCFA. Interestingly, VLCFAs affect to the largest degree the myelin-producing oligodendrocytes. In isolated mitochondria, VLCFAs exert a detrimental effect by affecting the inner mitochondrial membrane and promoting the permeability transition. In conclusion, we suggest that there is a potent toxic activity of VLCFA due to dramatic cell physiological effects with mitochondrial dysfunction and Ca2+ deregulation. This provides the first evidence for mitochondrial-based cell death mechanisms in neurodegenerative disease with peroxisomal defects and subsequent VLCFA accumulation.
authors.affiliation: Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Leipziger Strasse 44, D-39120 Magdeburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hein
authors.forename: Peter
authors.initials: P
authors.lastname: Schönfeld
authors.forename: Stefan
authors.initials: S
authors.lastname: Kahlert
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
mesh_terms: D000326:Adrenoleukodystrophy / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D020013:Calcium Signaling; D016923:Cell Death; D002478:Cells, Cultured; D005227:Fatty Acids / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009836:Oligodendroglia / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D017382:Reactive Oxygen Species