Cited by 182Metabolism and Genetic DisordersMitochondrial Function and PathologyLysosomal Storage Disorders Research

Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture

Hein, S., Schonfeld, P., Kahlert, S., Reiser, G.·2008·Human Molecular Genetics

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.

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Crossref · 10.1093/hmg/ddn066

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  • A direct cytotoxic effect on oligodendrocytes and astrocytes has been observed in rats following exposure to C26:0 lipids.

    “A direct cytotoxic effect on oligodendrocyte and astrocytes has been observed in rats, following exposure to C26:0 lipids (14).”

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Authors
Hein, S., Schonfeld, P., Kahlert, S., & Reiser, G.
Affiliations
Otto-von-Guericke-Universität Magdeburg (DE)
Corresponding author
Reiser, G.
Venue
Human Molecular Genetics
Published
2008-03-04
Volume
17
Issue
12
Pages
1750-1761
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
OpenAlex
W2167261850
Cited by
180
References
69
Citations by year
2026: 10 · 2025: 5 · 2024: 17 · 2023: 6 · 2022: 11 · 2021: 13 · 2020: 15 · 2019: 4 · 2018: 11 · 2017: 7 · 2016: 11 · 2015: 10 · 2014: 8 · 2013: 15 · 2012: 9
FWCI
5.98
Type
journal article
Language
en
Open access
closed
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
X-linked adrenoleukodystrophy, very long chain fatty acids, oligodendrocytes, astrocytes, hippocampus, mitochondrial depolarization, mitochondrial permeability transition, peroxisomal dysfunction, neurodegeneration, docosanoic acid, tetracosanoic acid, hexacosanoic acid, cell death
MeSH terms
Adrenoleukodystrophy, Animals, Astrocytes, Cells, Cultured, Fatty Acids, Hippocampus, Mitochondria, Neuroglia, Neurons, Oligodendroglia, Cell Death, Rats, Wistar, Reactive Oxygen Species, Calcium Signaling, Rats

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