PDE10A mutations help to unwrap the neurobiology of hyperkinetic disorders

Abstract

The dual-specific cAMP/cGMP phosphodiesterase PDE10A is exclusively localised to regions of the brain and specific cell types that control crucial brain circuits and behaviours. The downside to this expression pattern is that PDE10A is also positioned to be a key player in pathology when its function is perturbed. The last decade of research has seen a clear role emerge for PDE10A inhibition in modifying behaviours in animal models of psychosis and Huntington's disease. Unfortunately, this has not translated to the human diseases as expected. More recently, a series of families with hyperkinetic movement disorders have been identified with mutations altering the PDE10A protein sequence. As these mutations have been analysed and characterised in other model systems, we are beginning to learn more about PDE10A function and perhaps catch a glimpse into how PDE10A activity could be modified for therapeutic benefit.

Keywords: GAF domain; Huntington's disease; Hyperkinetic movement disorders; PDE10A; Striatum; cAMP.