HDAC6 is a target for protection and regeneration following injury in the nervous system

Abstract

Central nervous system (CNS) trauma can result in tissue disruption, neuronal and axonal degeneration, and neurological dysfunction. The limited spontaneous CNS repair in adulthood and aging is often insufficient to overcome disability. Several investigations have demonstrated that targeting HDAC activity can protect neurons and glia and improve outcomes in CNS injury and disease models. However, the enthusiasm for pan-HDAC inhibition in treating neurological conditions is tempered by their toxicity toward a host of CNS cell types -a biological extension of their anticancer properties. Identification of the HDAC isoform, or isoforms, that specifically mediate the beneficial effects of pan-HDAC inhibition could overcome this concern. Here, we show that pan-HDAC inhibition not only promotes neuronal protection against oxidative stress, a common mediator of injury in many neurological conditions, but also promotes neurite growth on myelin-associated glycoprotein and chondroitin sulfate proteoglycan substrates. Real-time PCR revealed a robust and selective increase in HDAC6 expression due to injury in neurons. Accordingly, we have used pharmacological and genetic approaches to demonstrate that inhibition of HDAC6 can promote survival and regeneration of neurons. Consistent with a cytoplasmic localization, the biological effects of HDAC6 inhibition appear transcriptionindependent. Notably, we find that selective inhibition of HDAC6 avoids cell death associated with pan-HDAC inhibition. Together, these findings define HDAC6 as a potential nontoxic therapeutic target for ameliorating CNS injury characterized by oxidative stressinduced neurodegeneration and insufficient axonal regeneration.HDAC inhibitor ͉ histone deacetylase ͉ neuroprotection ͉

Epigenetic Mechanisms in Cerebral Ischemia

“…67) and HDAC 6 (ref. 70) are rather situated in the cytoplasm, pointing to a possible involvement with non-histone targets.…”

Signaling Over Distances

“…Phosphorylation of DLK in response to nerve injury results in increased DLK abundance via reduction of DLK ubiquitination, which is mediated by the E3 ubiquitin ligase PHR1 and the de-ubiquitinating enzyme ubiquitin-specific protease 9X (USP9X), allowing a DLK signal to propagate back to the nucleus to enable a transcriptional stress response (46). Given the presence of several HDACs in axons (105,107,110), acetylation and deacetylation mecha-nisms are likely used in axons to regulate signaling. However, proteomics studies of subcellular compartments like axons, which is physiologically relevant for long-distance signaling present greater challenges because of the small amount of pure axonal material that can be analyzed.…”

Histone deacetylase inhibitor pracinostat in doublet therapy: a unique strategy to improve therapeutic efficacy and to tackle herculean cancer chemoresistance

“…Besides, the defined inhibitor is already available at the clinic for treating epilepsy, bipolar disorders, neuropathic pain apart from social phobias (Johannessen & Johannessen 2003;. HDACi have shown success in promoting neuroregeneration even under unfavourable neurite growth inhibitory conditions (Rivieccio et al 2009). …”