Therapeutic effects of HDAC3 inhibition on spinal injuries and autoimmune demyelinating diseases
Arnau Hervera, Molecular and Cellular Neurobiotechnology
The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration-competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration-incompetent central spinal cord injury does not. This dichotomic response offered us a unique opportunity to investigate the fundamental biological mechanisms underpinning this regenerative ability. Following a pharmacological screen with small molecule inhibitors targeting key epigenetic enzymes in DRG neurons we identified HDAC3 signaling as a novel candidate, that hindered axonal regenerative growth. In vivo, we found that only a peripheral but not a central axonal injury induced an increase in calcium, activating protein phosphatase 4 (PP4) who in turn dephosphorylates HDAC3 thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Additionally, we and others have found that, HDAC3 inhibition is able to modulate the neuroinflammatory environment in the CNS after injury. In that sense, after CNS injury, inflammatory phase transitions are poorly orchestrated leading to unresolved exaggerated inflammation that triggers secondary damage and functional deficits. We found that HDAC3 inhibition also altered the cytokinome after SCI, and we are currently characterizing the effects of this inhibition on the functions of different immune cells after SCI. Additionally, HDAC3 inhibition has been also previously described to play important roles in neuronal survival, lymphocyte differentiation and myelination, together with neuroinflammation, all these processes are essential regulators on the development and outcome of autoimmune demyelinating diseases, such as MS. In this direction, we are also currently studying the potential therapeutic effects of HDAC3 inhibition in the multiple sclerosis mouse model Experimental Autoimmune Encephalitis (EAE), as well as their underlying mechanisms, in neuroinflammation autoantigen presentation, lymphocyte differentiation, demyelination, remyelination and oligodendrocyte survival and differentiation.
This seminar will be held using the GoToMeeting app