HDAC inhibitors and neurodegeneration: at the edge between protection and damage

Abstract

The use of histone deacetylase inhibitors (HDACIs) as a therapeutic tool for neurodegenerative disorders has been examined with great interest in the last decade. The functional response to treatment with broad-spectrum inhibitors however, has been heterogeneous: protective in some cases and detrimental in others. In this review we discuss potential underlying causes for these apparently contradictory results. Because HDACs are part of repressive complexes, the functional outcome has been characteristically attributed to enhanced gene expression due to increased acetylation of lysine residues on nucleosomal histones. However, it is important to take into consideration that the up-regulation of diverse sets of genes (i.e. pro-apoptotic and anti-apoptotic) may orchestrate different responses in diverse cell types. An alternative possibility is that broad-spectrum pharmacological inhibition may target nuclear or cytosolic HDAC isoforms, with distinct non-histone substrates (i.e. transcription factors; cytoskeletal proteins). Thus, for any given neurological disorder, it is important to take into account the effect of HDACIs on neuronal, glial and inflammatory cells and define the relative contribution of distinct HDAC isoforms to the pathological process. This review article addresses how opposing effects on distinct cell types may profoundly influence the overall therapeutic potential of HDAC inhibitors when investigating treatments for neurodegenerative disorders.

Figure 1. Multicellular targets of HDACIs

This diagram illustrates the pleiotropic effects of HDACIs in multiple cell types. HDACIs can induce apoptosis in cancer cells (a), anti or pro-inflammatory effects in microglial cells (b), survival or apoptosis in neurons (c); inhibit the differentiation of oligodendrocyte progenitors (d); reduce inflammatory responses and induce protective effects of astrocytes (e); reduce inflammatory responses and induce immunosupression in lymphocytes (f). Additionally, HDACIs may affect axonal transport (upper right inset). Deacetylation of tubulin (depicted as removal of blue dots from microtubules) inhibits both anterograde (green) and retrograde transport (red). By preventing tubulin deacetylation HDACIs are able to restore transport.