I16 LXR signaling in the striatum and neuroprotection in Huntington’s disease

Le résumé fourni par la source

Huntington’s disease (HD) is associated to many cellular dysfunctions, including an alteration of cholesterol metabolism regulation with a decrease of its catabolization by the neuronal enzyme CYP46A1 into 24S-hydrocyholesterol, a natural ligand of LXR. CYP46A1 restoration in HD mice is neuroprotective and induces an upregulation of LXR target genes, suggesting their involvement in CYP46A1-mediated neuroprotection. The aim is now to study the effect of LXR activation in HD and to characterize newly synthetized LXR-beta agonists to target LXR-beta that are enriched in the brain without activating LXR-alpha isoform enriched in the liver. The bioactivity and neuroprotective role of agonists were studied in primary cultures of striatal neurons and astrocytes. zQ175 mice, a knock-in model of HD, were treated with LXR agonist and assessed for motor and cognitive behaviour. LXR agonists display transcriptional activity in neurons and astrocytes, and induce a neuroprotection in HD neurons by decreasing mHTT aggregates and increasing cell survival that are dependant on proteasome and autophagy activity. Motor phenotype of HD mice is not improved following LXR treatment. However, HD mice display an alteration of short-term memory and anxiety that are rescued by LXR treatment. The results support the biological efficacy of LXR compound and their neuroprotective role in HD. The next step will be to explore cellular and molecular mechanisms associated with anxiety-like phenotype in HD following LXR-treatment.

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