Don’t Take Away My P: Phosphatases as Therapeutic Targets in Huntington’s Disease

Abstract

The molecular bases that account for the preferential neurodegeneration of striatal mediumsized spiny neurons (MSNs) in Huntington’s Disease (HD) are still unknown, and different mechanisms have been proposed to contribute to the neurodegenerative process. These include mitochondrial dysfunction and metabolic impairment, transcriptional dysregulation, altered expression of trophic factors, dopamine toxicity, oxidative stress, and changes in autophagy, and huntingtin (htt) phosphorylation. In addition, excitotoxicity through the overactivation of N-methyl-D-aspartate (NMDA) receptors (NMDARs) has also been proposed to contribute to the preferential loss of these neurons (for review see Ehrnhoefer et al., 2011; Jin & Johnson, 2010; Perez-Navarro et al., 2006; Renna et al., 2010; Rosenstock et al., 2010; Weir et al., 2011). Some of these mechanisms are controlled by the attachment/removal of phosphate groups through the action of protein kinases and protein phosphatases, respectively. Therefore, alterations in their levels/activity in the presence of mutant htt (mhtt) can impact on cell survival...