Huntington’s disease (HD) is caused by expanded poly-glutamine in Huntingtin (mHTT), inducing many cellular dysfunctions, including cholesterol metabolism deregulation. The main pathway of cholesterol elimination is its catabolization by the neuronal 24-hydroxylase enzyme (CYP46A1) into 24S-hydroxycholesterol (24S-OHC), a ligand of Liver X Receptor (LXR). CYP46A1 level is decreased in HD, and its restoration induces a neuroprotection with an upregulation of LXR target genes. A therapeutic interest was raised for the LXR in several neurodegenerative diseases. We hypothesized the involvement of LXR in CYP46A1 neuroprotection. There are two LXR isoforms, LXRalpha mainly expressed in liver and LXRbeta enriched in the brain for cholesterol metabolism regulation. Commercialized LXR agonists suffer from side effects on lipogenesis due to the activation of LXRalpha in the liver. The aim of the project is to take advantage of new LXRbeta agonists to investigate the role of LXR activation in HD. Primary cultures of striatal neurons and astrocytes were treated with LXR agonists to validate their bioactivity and study their neuroprotective role in a HD cellular model. Wild Type mice were treated with LXR commercial agonist to determine the more efficient administration root and protocol. In neurons and astrocytes culture, LXRalpha, LXRbeta and commercial agonists induce an increase of mRNA level of LXR target genes, involved in cholesterol metabolism and known to be downregulated in HD. The LXR agonists induce a neuroprotection in HD striatal neurons in culture, with a decrease of mHTT aggregates and an increase of cell survival. When treated with inhibitor of proteasome or autophagy machinery, the neuroprotective role induced by LXR agonists is reversed.

These results support the biological efficacy of these new LXR compounds and their neuroprotective role in HD striatal neurons. The next step will be to explore their effect in HD mice model.