Liver X Receptor Identified as Therapeutic Target for Treatment of Parkinson's Disease

The liver X receptors (nuclear receptor subfamily 1, group H, member 2), LXRalpha and LXRbeta, form a subfamily of the nuclear receptor superfamily and are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. The inducible LXRalpha is highly expressed in liver, adrenal gland, intestine, adipose tissue, macrophages, lung, and kidney, whereas LXRbeta is ubiquitously expressed.

To determine the function of LXRbeta in brain tissues the investigators genetically engineered a line of mice lacking the gene for synthesis of this receptor. These modified mice and a matching group of normal, wild type mice were then exposed to the drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is a neurotoxin that damages the brain in ways that closely mimic Parkinson's disease.

Results published in the July 23, 2012, online edition of the journal Proceedings of the National Academy of Sciences of the USA (PNAS) revealed that the dopamine-producing neurons of the substantia nigra of the genetically engineered mice were much more severely affected by MPTP than were those of the wild type controls. In addition, the number of activated microglia and astrocytes was higher in the substantia nigra of the modified mice than in the controls. Administration of the LXR-activating drug GW3965 to MPTP-treated control mice protected against loss of dopamine-producing neurons and fibers projecting to the striatum, and resulted in fewer activated microglia and astroglia.

"LXRbeta performs an important function in the development of the central nervous system, and our work indicates that the presence of LXRbeta promotes the survival of dopaminergic neurons, which are the main source of dopamine in the central nervous system," said senior author Dr. Jan-Ake Gustafsson, professor of biosciences and nutrition at the University of Houston. "The receptor continues to show promise as a potential therapeutic target for this disease, as well as other neurological disorders."

"LXRbeta is not expressed in the dopamine-producing neurons, but instead in the microglia surrounding the neurons," said Dr. Gustafsson. "Microglia are the police of the brain, keeping things in order. In Parkinson's disease the microglia are overactive and begin to destroy the healthy neurons in the neighborhood of those neurons damaged by MPTP. LXRbeta calms down the microglia and prevents collateral damage. Thus, we have discovered a novel therapeutic target for treatment of Parkinson's disease."

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