Alpha-synuclein is a lipid-binding protein expressed in neurons and oligodendrocytes which is increased in Parkinson's disease. We identified two putative liver X receptor (LXR) response elements in the human oc-synuclein gene and used synthetic (TO901317, GW3695) and physiological (27-hydroxycholesterol) LXR activators to assess regulation of α-synuclein. LXR ligands upregulated α-synuclein m RNA by two-five-fold in human SK-N-SH neurons and three-six-fold in human MO3.13 oligodendrocytes. Significant 50% to four-fold induction of α-synuclein protein was also detected. Under these conditions, m RNA for LXR-responsive gene ABCAI was significantly upregulated 15-40-fold and 5-25-fold in neurons and oligodendrocytes, respectively. LXR may, therefore, contribute to the regulation of α-synuclein expression in neurons and oligodendrocytes. © 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.