Evidence of defective cholesterol metabolism in ALS
Creators: name: Abdel-Khalik, Jonas
name: Eylan Yutuc
name: Crick, Peter J.
name: Jan-Ake Gustafsson
name: Warner, Margaret
name: Roman, Gustavo
name: Talbot, Kevin
name: Gray, Elizabeth
name: Turner, Martin R.
name: Griffiths, William J.
name: Yuqin Wang
Publisher: name: F1000Research
Year: 2016

description: Background<br>For the development of effective disease-modifying therapies for ALS, reliable markers of disease activity are a research priority. High plasma levels of cholesterol have been suggested to be neuroprotective for ALS, associated with an increased survival time [1]. The gene <i>CYP27A1</i>, encoding cholesterol (25R)26-hydroxylase, the enzyme initiating extra-hepatic metabolism of cholesterol through bile acid biosynthesis, was recently identified as a susceptibility gene for sporadic ALS [2]. In addition, statins, cholesterol lowering drugs which inhibit HMG-CoA reductase, have been suggested to accelerate functional decline in ALS patients [3]. Cholesterol is also a major component of neurons, hence this sterol and its metabolites are candidate biomarkers of neurodegeneration in ALS on several levels.<br><br>Objectives<br>To quantify sterols and their metabolites in CSF from ALS patients.<br><br>Methods<br>CSF from 20 ALS patients from the Oxford Study for Biomarkers in MND (BioMOx) and 15 controls were assayed for &gt;50 different sterols using quantitative liquid chromatography – mass spectrometry (LC-MS) [4].<br><br>Results<br>The CSF concentration of cholesterol was elevated in ALS compared with controls (P &lt; 0.01). When metabolite levels were normalised to cholesterol, the metabolite 3β,7α-dihydroxycholest-5-en-26-oic acid (P &lt; 0.05) along with its precursor 3β-hydroxycholest-5-en-26-oic acid (P &lt; 0.01) and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid (P &lt; 0.01) were reduced in concentration. These three acids are members of the acidic pathway for bile acid biosynthesis.<br><br>Discussion and Conclusions<br>Levels of cholesterol are tightly regulated in brain by a balance between synthesis and metabolism. The blood brain barrier prevents direct import and export of cholesterol from and to the circulation. When neurons die, cholesterol is released. In the healthy state cholesterol is metabolised to hydroxycholesterols which enter the bile acid biosynthesis pathway, members of which can cross the blood brain barrier and be exported. Our results indicate that the acidic branch of bile acid biosynthesis may be defective in ALS, leading to a failure of the CNS to remove excess cholesterol. Importantly, neither elevated CSF cholesterol levels nor reduced metabolite levels were found in Alzheimer’s disease, vascular dementia or multiple sclerosis patients [5]. Our ALS data may be important on two fronts, (i) excess cholesterol is known to be toxic to neuronal cells, and (ii) 3β,7α-dihydroxycholest-5-en-26-oic acid has been shown to be neuroprotective towards motor neurons [6].<br><br><br>References<br>1. Dorst J, Kühnlein P, Hendrich C <i>et al</i>  J Neurol 2011; 258:613-7.<br>2. Diekstra FP, Saris CG, van Rheenen W <i>et al </i>PLoS One 2012; 7:e35333.<br>3. Zheng Z, Sheng L, Shang H Amyotroph Lateral Scler Frontotemporal Degener 2013; 14:241-5.<br>4. Crick PJ, Bentley WT, Abdel-Khalik J <i>et al</i> Clin Chem 2015; 61:400-11.<br>5. Griffiths WJ, Wang Y, Abdel-Khalik J <i>et al</i> unpublished studies.<br>6. Theofilopoulos S, Griffiths WJ, Crick PJ <i>et al</i> J Clin Invest 2014; 124:4829-42.<br>