25-Hydroxycholesterol is involved in the pathogenesis of amyotrophic lateral sclerosis

Abstract

This study aimed to evaluate the levels of three major hydroxycholesterols (24-, 25-, and 27-hydroxycholesterols) in the serum and cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS), as well as to show their role in the pathogenesis of ALS experimental models. The level of 25-hydroxycholesterol were higher in untreated ALS patients (n = 30) than in controls without ALS (n = 33) and ALS patients treated with riluzole (n = 9) both in their serum and CSF. The level of 25-hydroxycholesterol in the serum of ALS patients were significantly associated with their disease severity and rate of progression. In the motor neuron-like cell line (NSC34) with the human mutant G93A superoxide dismutase 1 gene (mSOD1-G93A), 25-hydroxycholesterol induced motor neuronal death/ apoptosis via glycogen synthase kinase-3β and liver X receptor pathways; riluzole treatment attenuated these effects. The expressions of enzymes that synthesize 25-hydroxycholesterol were significantly increased in the brains of early symptomatic mSOD1G93A mice. Our data, obtained from patients with ALS, a cellular model of ALS, and an animal model of ALS, suggests that 25-hydroxycholesterol could be actively involved in the pathogenesis of ALS, mostly in the early symptomatic disease stage, by mediating neuronal apoptosis.

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

“…Lipid composition is studied mainly by liquid chromatography/mass spectrometry (LC/MS), gas chromatography/mass spectrometry (GC/MS), or nuclear magnetic resonance (NMR)-based techniques and is a part of metabolomics (Wenk, 2005). However, only 25-HC serum shows significant negative correlation with the ALSFRS-R score that determines the progression rate; thus, it represents a potential new biomarker (Kim et al, 2017). In addition, 25-HC induces apoptosis and neuronal death in the motor neuron-like cell line (NSC34), and therefore it appears to be actively involved in the ALS pathogenesis.…”

“…The level of 25‐HC in the serum of ALS was significantly associated with disease severity and progression. However, only 25‐HC serum shows significant negative correlation with the ALSFRS‐R score that determines the progression rate; thus, it represents a potential new biomarker (Kim et al., ). In addition, 25‐HC induces apoptosis and neuronal death in the motor neuron‐like cell line (NSC34), and therefore it appears to be actively involved in the ALS pathogenesis.…”

“…In addition, 25‐HC induces apoptosis and neuronal death in the motor neuron‐like cell line (NSC34), and therefore it appears to be actively involved in the ALS pathogenesis. Also, the expression of enzymes that synthesize 25‐HC is significantly increased in the brains of the early symptomatic SOD1 G93A mice (Kim et al., ).…”

Lipid-derived electrophiles induce covalent modification and aggregation of Cu,Zn-superoxide dismutase in a hydrophobicity-dependent manner

“…Our data specifically bear evidence that lipid electrophile hydrophobicity is critical to ligand-induced SOD1 aggregation. Given the massive abundance of cholesterol in brain tissues 29 and the solid link between cholesterol metabolism and neurodegenerative diseases, 77,78 in vivo experiments with cells or animal models may provide additional clues on the role of highly hydrophobic secosterol aldehydes in protein aggregation.…”

Determination of total plasma oxysterols by enzymatic hydrolysis, solid phase extraction and liquid chromatography coupled to mass-spectrometry

“…Likewise, oxysterols have been a matter of intense research in the nervous system, where their accumulation has been found to modify oxidative stress [7], apoptosis [8] and cell death in several types of neural cells such as PC12 cells [9,10] and sympathetic [11], retinal [12] and cerebellar [13] neurons. 25-HC has also been proposed as a marker of Alzheimer's disease progression due to its ability to modulate choline acetyltransferase [14] and an etiological agent in amyotrophic lateral sclerosis [15]. Finally, 25-HC has been found to regulate the activity of estrogen receptors alpha and beta [16], which could cause reproductive disorders.…”