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. 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. Amyotrophic lateral sclerosis (ALS) is a heterogeneous, progressive, and fatal neurodegenerative disease characterized by variable loss of upper and lower motor neurons (1Kiernan M.C. Vucic S. Cheah B.C. Turner M.R. Eisen A. Hardiman O. Burrell J.R. Zoing M.C. Amyotrophic lateral sclerosis.Lancet. 2011; 377: 942-955Abstract Full Text Full Text PDF PubMed Scopus (1797) Google Scholar). Biomarkers that are sensitive to the progression of disease have the potential to shorten therapeutic trials and provide new drug targets. Study of the metabolome offers the potential to identify disease-specific patterns for ALS, possibly providing such biomarkers and new insights into the deranged biochemical pathways associated with ALS. Metabolomic studies in blood and cerebrospinal fluid (CSF) have been performed utilizing proton nuclear magnetic resonance spectrometry (2Gray E. Larkin J.R. Claridge T.D. Talbot K. Sibson N.R. Turner M.R. 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L. et for sterol and Chem. 2015; PubMed Scopus Google and in serum and of to or product of not and to to not and to to to to of and its product of and its product not and not and to to to not of The to product of not and The to The to of and its product of and its product to in a new not was from patients with ALS patients with lateral sclerosis and CSF was from ALS patients and controls and CSF were from ALS and patients and healthy and as part of The Study for Biomarkers in and the of ALS and to and the was by the B. CSF for development were from a performed of serum was to a of of of of of of of and of sterols from with in an of was to the a of the was for separate cholesterol from the more oxysterols and acids, the sample in of was a with of and of The through the was a of by the by a The was with a of to in which and was by with a of cholesterol and sterols of was with of a in of was lipid more than cholesterol was into and and to that a hydrolysis step was not included in the sample preparation and by cholesterol from its metabolites in the first step of sample with is was in of sample was of was of cholesterol from in The was for which the was with of were to but in the of cholesterol of acid was to and and of P.J. T. J. I. C. L. L. et for sterol and Chem. 2015; PubMed Scopus Google Scholar), was to of was to to for LC/MS (supplemental Fig. the was to in the remove excess a was with of of and of the were The sample was with of and the was to the of was to the and the of was with of to of was to the by a of the with of The of was with of to a of the to the the by which and were by the whereas to of was to the and acids, and more nonpolar sterols were from the with and of and in the first from the Cholesterol and sterols of of and acid analysis by an of from and was in cholesterol analysis of from and were In both the in was with to a concentration of the of the during Analysis was performed a with an and a system as described (22Griffiths W.J. Crick P.J. Wang Y. Ogundare M. Tuschl K. Wang Y. for of ligands in Biol. 2013; PubMed Scopus Google Scholar, P.J. T. J. I. C. L. L. et for sterol and Chem. 2015; PubMed Scopus Google Scholar). to were high-resolution maximum in the in with to in the was performed by or by structural of CSF was to of of of of of of and of with in an of was and the was for by for The CSF sample in of was a as in the serum the was with a of of to in which and The of the sample preparation including was to that for with the that the from were and in to sample the An was for were performed the in the are for sterol analysis (22Griffiths W.J. Crick P.J. Wang Y. Ogundare M. Tuschl K. Wang Y. for of ligands in Biol. 2013; PubMed Scopus Google Scholar) in with LC/MS with serum from patients with ALS and patients with the upper motor of ALS, were compared with the of nonesterified cholesterol, of its and metabolites were (see Table for and and Table for that a hydrolysis step was not are for nonesterified We to in the sample and included both in the was in the of cholesterol or its or between ALS, or samples. the concentration of as the of and its which are The is an product of W.J. J. Crick P.J. Ogundare M. Tuschl K. A. et and oxysterols in plasma from Steroid Biochem. Mol. Biol. 2016; of 2016; Scholar). was in the concentration of the metabolite in serum of the ALS patients compared with controls The first of cholesterol metabolism to known as pathway, in to by metabolism to and Fig. was elevated in ALS serum and are the first of the of bile acid biosynthesis The and of bile acid Biochem. PubMed Scopus Google a in concentration between ALS, or and or and be via of cholesterol, and metabolites have been suggested as of stress L. S. S. M. W. L. of oxysterols and in plasma and as of stress Biochem. PubMed Scopus Google of cholesterol metabolism by the and in sterols concentration in CSF and serum are by and The of to the of the the are are as bile or enzyme sterol were performed the the first of the extrahepatic part of the acidic of bile acid biosynthesis, was in ALS and serum compared with controls as was 3β-hydroxycholest-5-en-26-oic acid in ALS serum CYP27A1 is the enzyme responsible for of cholesterol and to the acid. that the systematic E. S. Brown R.C. Y. W. et system for Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar), of the of the cholesterol in it On the and of 2012; PubMed Scopus Google Scholar). is The for in the of the of its is of in the circulation are to cholesterol, with cholesterol levels associated with levels of A. S. B. N. J. K. M. 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Horvath S. et al.Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS.PLoS One. 2012; 7: e35333Crossref PubMed Scopus (43) Google Scholar). in CYP27A1 leading to a defective CYP27A1 enzyme are the of the neurodegenerative of bile acid 2011; PubMed Scopus Google Scholar). for a for oxysterols in from the by et cholesterol molecules to of and by the sterol cholesterol biosynthesis A. G. of 2014; PubMed Scopus Google Scholar). it been that inhibit cholesterol biosynthesis Y. S. J. W.J. The of cholesterol homeostasis in changes to the Proteome Res. 2008; 7: PubMed Scopus Google Scholar), reduced levels of in the as in ALS, in cholesterol biosynthesis and and In have identified elevated cholesterol in the CSF of ALS When normalized to cholesterol, of acidic metabolites are but cholesterol metabolites imported from the circulation are data to of the CYP27A1 enzyme leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective and other ligands The of the for for with amyotrophic lateral sclerosis cerebrospinal fluid cytochrome P450 lateral sclerosis 3β-hydroxycholest-5-en-26-oic acid 3β,7α-dihydroxycholest-5-en-26-oic acid acid 7α-hydroxy-3-oxocholest-4-en-26-oic acid