HDAC4 Promotes Neuroprotection of Retinal Ganglion Cells After Optic Nerve Injury

Purpose: As the sole retinal output neurons, retinal ganglion cells (RGCs) transmit all visual information from the retina to the brain. RGCs do not regenerate, and effective therapies for promoting RGC survival and axon regeneration in glaucoma and other optic neuropathies comprise an unmet clinical need. Histone deacetylases (HDACs) are epigenetic modifiers that repress gene transcription. Here, we identify a role for HDAC4 in RGC neurodegeneration and axon regeneration. Methods: The role of HDAC4 in RGC neuroprotection and axon regeneration was studied in the mouse optic nerve crush (ONC) model for optic neuropathy by RGC transduction in vivo with adeno-associated virus vectors. RGC gene expression in vivo was studied by single cell RNA sequencing (scRNA-seq). Results: A loss-of-function screen identified HDAC4 as essential for RGC survival after ONC injury. Expression of a nuclear-localized HDAC4 missense mutant (HDAC4 3SA) increased RGC survival and axon regeneration after ONC injury. Similar beneficial effects were conferred by an N-terminal fragment of HDAC4 (HDAC4 NT) that can constitutively repress gene expression. The scRNA-seq showed that 1 day after ONC injury, RGC transcriptomic profiles were altered such that HDAC4 NT and to a lesser degree the HDAC4 3SA mutant attenuated the gene expression changes associated with injury. Conclusions: Enhancement of HDAC4 activity promotes RGC survival and axon regeneration in a model of RGC injury, normalizing RGC gene expression toward the uninjured state. HDAC4 is thereby identified as a novel target in the development of therapeutics for RGC protection and restoration of visual function.