Nuclear receptors in neurodegenerative diseases

Abstract

Nuclear receptors have generated substantial interest in the past decade as potential therapeutic targets for the treatment of neurodegenerative disorders. Despite years of effort, effective treatments for progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and ALS remain elusive, making non-classical drug targets such as nuclear receptors an attractive alternative. A substantial literature in mouse models of disease and several clinical trials have investigated the role of nuclear receptors in various neurodegenerative disorders, most prominently AD. These studies have met with mixed results, yet the majority of studies in mouse models report positive outcomes. The mechanisms by which nuclear receptor agonists affect disease pathology remain unclear. Deciphering the complex signaling underlying nuclear receptor action in neurodegenerative diseases is essential for understanding this variability in preclinical studies, and for the successful translation of nuclear receptor agonists into clinical therapies.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Huntington's disease; Inflammation; Liver X receptors; Microglia; Neurodegeneration; Nuclear receptors; Parkinson's disease; Peroxisome proliferator-activated receptors; Retinoid X receptors.

Figure 1. Nuclear receptors are ligand-activated transcription factors

Nuclear receptors (type II) form obligate heterodimers with RXR and comprise the functional transcription factor. The nuclear receptor complex transactivates its target genes by binding to sequence specific elements in their promoters. Ligand binding results in dismissal of a corepressor complex and association with coactivators, resulting in transcription of the target gene. Nuclear receptors can also act as transrepressors. Sumoylation induces their direct association with NFkB positioned on the promoters of proinflammatory genes, preventing the dismissal of corepressor complexes and the initiation of transcription.