Defective cholesterol metabolism in amyotrophic lateral sclerosis.
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.
Swansea University Medical School, Swansea, United Kingdom.
Jonas
J
Abdel-Khalik
Swansea University Medical School, Swansea, United Kingdom.
Eylan
E
Yutuc
Swansea University Medical School, Swansea, United Kingdom.
Peter J
PJ
Crick
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX.
Jan-Åke
JÅ
Gustafsson
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX.
Margaret
M
Warner
Methodist Neurological Institute, Methodist Hospital, Houston, TX.
Gustavo
G
Roman
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Kevin
K
Talbot
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Elizabeth
E
Gray
Swansea University Medical School, Swansea, United Kingdom w.j.griffiths@swansea.ac.uk martin.turner@ndcn.ox.ac.uk y.wang@swansea.ac.uk.
William J
0000-0002-4129-6616
WJ
Griffiths
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom w.j.griffiths@swansea.ac.uk martin.turner@ndcn.ox.ac.uk y.wang@swansea.ac.uk.
Martin R
MR
Turner
Swansea University Medical School, Swansea, United Kingdom w.j.griffiths@swansea.ac.uk martin.turner@ndcn.ox.ac.uk y.wang@swansea.ac.uk.
Yuqin
Y
Wang
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000473:pathology; D001647:Bile Acids and Salts / Q000097:blood / Q000134:cerebrospinal fluid / Q000302:isolation & purification*; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood / Q000134:cerebrospinal fluid / Q000302:isolation & purification*; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood / Q000134:cerebrospinal fluid / Q000302:isolation & purification*; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000097:blood / Q000134:cerebrospinal fluid / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology
D001647:Bile Acids and Salts; D008055:Lipids; D002784:Cholesterol
bile acids and salts/biosynthesis; brain lipids; cholestenoic acids; cytochrome P450; mass spectrometry; neurodeneneration.; nuclear receptors/LXR; oxysterols