I024 Liver X receptor activation is associated with behavioural and neuropathological improvements in Huntington’s disease
Year: 2024
Type: conference-abstract
Abstract: Huntington’s disease (HD) is associated to many cellular dysfunctions, including a reduction cholesterol catabolism by CYP46A1 into 24S-hydroxycholesterol, a natural ligand for the nuclear receptors LXR (Liver X Receptor). CYP46A1 restoration in HD mice is neuroprotective and upregulates LXR target genes, suggesting their involvement. Our aim was to study the effect of LXR activation by a synthetic ligand (T0901317) on HD pathogenesis through an integrative preclinical analysis. LXR activation was neuroprotective in a HD cellular model and chronic treatment of symptomatic HD mice alleviated weight loss and restored cognitive and psychiatric-like alterations (social interaction, depression-like). This behavioural effect was associated to a transcriptional correction of genes involved in striatal neurons identity and function, hippocampal neurotransmission, plasticity and BDNF signalling. In particular, Bdnf mRNA level in the dentate-gyrus was restored specifically in neurons, which was associated with a rescue of adult neurogenesis and a reduction of mHTT inclusions. We reasoned that the effect of T0901317 on behavioural alterations in HD could involve these molecular regulations, however the repeated use of T0901317 is limited by side effects in periphery due to LXR activation in the liver. Therefore, we then used a new ligand to target the brain-specific LXR isoform, as we illustrated by in silico modelling analysis. We validated its transcriptional bioactivity and neuroprotective effects in HD cellular model, as well as its beneficial effect on cognitive alterations in HD mice. Cellular mechanisms are being investigating. Overall, our results provide strong evidence to consider LXR as a novel therapeutic target for HD.
Authors: Coline Mounier, Katleen Pinchaud, Cameron Hery, Maïalen Arietta Lobo, Weixuan Xue, Laurent Le Corre, Cloé Mendoza, Jean-François Gilles, Maura Marinozzi, Nicolas Heck, Ludovic Tricoire, Nicolas Pietrancosta, Céline Baligand, Carole Escartin, Peter Vanhoutte, Jocelyne Caboche, Christian Néri, Sandrine Betuing
Institutions: Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Institut de Biologie Paris-Seine, Neurosciences Paris-Seine, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, Laboratoire des Maladies Neurodégénératives, Molecular Imaging Research Center, Université Paris Cité, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, University of Perugia
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402374353