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

Abstract

// Sung-Min Kim 1, * , Min-Young Noh 3, * , Heejaung Kim 2 , So-Young Cheon 1 , Kang Mi Lee 4 , Jaeick Lee 4 , Eunju Cha 4 , Kyung Seok Park 1, 2 , Kwang-Woo Lee 1 , Jung-Joon Sung 1 , Seung Hyun Kim 3 1 Department of Neurology, Seoul National University, College of Medicine, Seoul, Korea 2 Department of Neurology, Seoul National University Bundang hospital, Seong Nam, Korea 3 Department of Neurology, Hanyang University, College of Medicine, Seoul, Korea 4 Doping Control Center, Korea Institute of Science and Technology, Korea * These authors have contributed equally to this work Correspondence to: Seung Hyun Kim, email: kimsh1@hanyang.ac.kr Jung-Joon Sung, email: jjsaint@snu.ac.kr Keywords: amyotrophic lateral sclerosis, cholesterol, hydroxycholesterol, 25-hydroxycholesterol, liver X receptor Received: July 10, 2016      Accepted: December 16, 2016      Published: January 02, 2017 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.