Human Molecular Genetics Advance Access published online on March 14, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn066
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Toxic effects of X- linked adrenoleukodystrophy (X-ALD)-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture
1 Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Leipziger Str. 44, D-39120 Magdeburg 2 Institut für Biochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Leipziger Str. 44, D-39120 Magdeburg, Germany
* Correspondence to: Prof. Dr. G. Reiser, Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Leipziger Straße 44, 39120 Magdeburg, Germany, Phone: +49-391-6713088, Fax: +49-391-6713097 Email: georg.reiser{at}med.ovgu.de
Received December 21, 2007; Revised February 18, 2008; Accepted February 2, 2008
Saturated very long chain fatty acids (VLCFA; 
C22:0) accumulate in X-linked adrenoleukodystrophy (X-ALD, OMIM 300100
[OMIM]
), a severe hereditary neurodegenerative disease, due to peroxisomal impairment. Previous studies analyzed 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 remains still unclear. To understand the toxic effects of VLCFA in the brain, here, we exposed neural cells to VLCFA and analyzed the cellular consequences. We found that oligodendrocytes and astrocytes challenged with docosanoic- (C22:0), tetracosanoic- (C24:0) and hexacosanoic acid (C24:0), die within 24 h. VLCFA-induced depolarisation of mitochondria in-situ and increased intracellular Ca2+ level in all three brain cell types provide indications about the mechanism of toxicity of VLCFA. Interestingly, VLCFA affect to the largest degree the myelin-producing oligodendrocytes. In isolated mitochondria, VLCFA 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 dramatic cell physiological effects with mitochondrial dysfunction and Ca2+ deregulation. This, provides the first evidence for mitochondrially-based cell death mechanisms in neurodegenerative disease with peroxisomal defects and subsequent VLCFA accumulation.
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