Liver X receptors: from cholesterol regulation to neuroprotection—a new barrier against neurodegeneration in amyotrophic lateral sclerosis?

Abstract

Cholesterol plays a central role in numerous nervous system functions. Cholesterol is the major constituent of myelin sheaths, is essential for synapse and dendrite formation, axon guidance as well as neurotransmission. Among regulators of cholesterol homeostasis, liver X receptors (LXRs), two members of the nuclear receptor superfamily, play a determinant role. LXRs act as cholesterol sensors and respond to high intracellular cholesterol concentration by decreasing plasmatic and intracellular cholesterol content. Beyond their cholesterol-lowering role, LXRs have been proposed as regulators of immunity and anti-inflammatory factors. Dysregulation of cholesterol metabolism combined to neuroinflammatory context have been described in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS is characterized by the progressive loss of motoneurons in the brain and spinal cord, leading to severe paralytic condition and death of patients in a median time of 3 years. Motoneuron degeneration is accompanied by chronic neuroinflammatory response, involving microglial and astrocytic activation, infiltration of blood-derived immune cells and release of pro-inflammatory factors. We propose to discuss here the role of LXRs as a molecular link between the central nervous system cholesterol metabolism, neuroinflammation, motoneuron survival and their potential as promising therapeutic candidates for ALS therapy.

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

“…In a cohort of 438 patients with ALS and 330 healthy controls, the LXRβ single nucleotide polymorphism rs2695121 was associated with a 30% increase of ALS duration . Taken together, these data suggest that LXRs might link cholesterol homeostasis and neurodegeneration, involving neuroinflammation .…”

“…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]. We speculate that the low binding activity of ApoE2 for LDL receptor impairs cholesterol transport from astrocytes to neurons, leading to defective cholesterol metabolism and finally to a decrease in LXRb ligands in neurons.…”

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.…”

“…LXRs are nuclear receptors for oxysterols, which regulate cholesterol synthesis among other cellular processes (dependent on the cellular type). A recent study identified two single nucleotide polymorphisms of LXR-α, rs2279238 and rs7120118, associated with delayed age of ALS onset amongst a cohort of 330 ALS patients (Mouzat et al, 2016). Moreover, male LXR-β −/− mice develop severe motor impairment closely resembling ALS at 7 months which later progresses to hind-limb paralysis (Andersson, Gustafsson, Warner, & Gustafsson, 2005).…”