Defective cholesterol metabolism in amyotrophic lateral sclerosis

• Published in: Journal of lipid research Vol. 58; no. 1; pp. 267 - 278
• Main Authors: Abdel-Khalik, Jonas, Yutuc, Eylan, Crick, Peter J., Gustafsson, Jan-Åke, Warner, Margaret, Roman, Gustavo, Talbot, Kevin, Gray, Elizabeth, Griffiths, William J., Turner, Martin R., Wang, Yuqin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2017; Journal of Lipid Research; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Acids; Aged; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - blood; Amyotrophic Lateral Sclerosis - cerebrospinal fluid; Amyotrophic Lateral Sclerosis - pathology; Bile; Bile Acids and Salts - blood; Bile Acids and Salts - cerebrospinal fluid; Bile Acids and Salts - isolation & purification; bile acids and salts/biosynthesis; brain lipids; Central nervous system; Central Nervous System - metabolism; Central Nervous System - pathology; Cerebrospinal fluid; cholestenoic acids; Cholesterol; Cholesterol - blood; Cholesterol - cerebrospinal fluid; Cholesterol - isolation & purification; cytochrome P450; Female; Humans; Lipid metabolism; Lipids - blood; Lipids - cerebrospinal fluid; Lipids - isolation & purification; Male; mass spectrometry; Metabolites; Middle Aged; Nerve Degeneration - blood; Nerve Degeneration - cerebrospinal fluid; Nerve Degeneration - pathology; Neurodegeneration; neurodeneneration; Neurons - metabolism; Neurons - pathology; Neuroprotection; nuclear receptors/LXR; oxysterols; Patient-Oriented and Epidemiological Research; Sterols; cholestenoic acids; brain lipids; neurodeneneration; bile acids and salts/biosynthesis; oxysterols; nuclear receptors/LXR; mass spectrometry; cytochrome P450
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.P071639

As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3β,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3β-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3β-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3β,7α-dihydroxycholest-5-en-26-oic acid.