Liver X Receptor Genes Variants Modulate ALS Phenotype

Abstract

Amyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. Phenotype of ALS patients is highly variable and may be influenced by modulators of energy metabolism. Recent works have implicated the liver X receptors α and β (LXRs), either in the propagation process of ALS or in the maintenance of MN survival. LXRs are nuclear receptors activated by oxysterols, modulating cholesterol levels, a suspected modulator of ALS severity. In a cohort of 438 ALS patients and 330 healthy controls, the influence of LXR genes on ALS risk and phenotype was studied using single nucleotide polymorphisms (SNPs). The two LXRα SNPs rs2279238 and rs7120118 were shown to be associated with age at onset in ALS patients. Consistently, homozygotes were twice more correlated than were heterozygotes to delayed onset. The onset was thus delayed by 3.9 years for rs2279238 C/T carriers and 7.8 years for T/T carriers. Similar results were obtained for rs7120118 (+2.1 years and +6.7 years for T/C and C/C genotypes, respectively). The LXRβ SNP rs2695121 was also shown to be associated with a 30% increase of ALS duration (p = 0.0055, FDR = 0.044). The tested genotypes were not associated with ALS risk. These findings add further evidence to the suspected implication of LXR genes in the disease process of ALS and might open new perspectives in ALS therapeutics.

Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease

“…In ALS, disruptions to LXR signaling have been implicated in dysfunctional signaling cascades, leading to motor neuron and glial cell damage in SOD1 mice. LXR knockout mice show neuroinflammatory responses leading to motor neuron loss, and neuromuscular junction defects (Mouzat et al, 2017 ). A number of PUFAs also act as pro- or anti-inflammatory signaling molecules.…”

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

“…Furthermore, a dissection of oxysterol signalling could, per se, lead to identification of potential therapeutic avenues in neurodegeneration. The genetic evidence in ALS supporting this is as strong as that from studies with SOD1 mutants and LXR-β −/− mice: Lack of ROS neutralization and dysregulated oxysterol signalling leads to motor neuron degeneration Mouzat et al, 2016;Mouzat et al, 2018).…”

“…The genetic evidence in ALS supporting this is as strong as that from studies with SOD1 mutants and LXR-β −/− mice: Lack of ROS neutralization and dysregulated oxysterol signalling leads to motor neuron degeneration Mouzat et al, 2016;Mouzat et al, 2018). Furthermore, a dissection of oxysterol signalling could, per se, lead to identification of potential therapeutic avenues in neurodegeneration.…”

Correlation between Apolipoprotein E genotype and brain metabolism in amyotrophic lateral sclerosis

“…Data from in-vitro studies and animal models suggest that specific cholestenoic acids, intermediates in the conversion of cholesterol into bile acids, can activate LXRs, helping motor neuron survival [35]. In a cohort of 438 patients with ALS and 330 healthy controls, the LXRb single nucleotide polymorphism rs2695121 was associated with a 30% increase of ALS duration [36]. Taken together, these data suggest that LXRs might link cholesterol homeostasis and neurodegeneration, involving neuroinflammation [37].…”