HDAC5 promotes optic nerve regeneration by activating the mTOR pathway

Neurons in the central nervous system (CNS) regenerate poorly compared to their counterparts in the peripheral nervous system. We previously showed that, in peripheral sensory neurons, nuclear HDAC5 inhibits the expression of regenerative associated genes. After nerve injury, HDAC5 is exported to the cytoplasm to promote axon regeneration. Here we investigated the role of HDAC5 in retinal ganglion cells (RGCs), a CNS neuron which fails to survive and regenerate axons after injury. In contrast to PNS neurons, we found that HDAC5 is mostly cytoplasmic in naïve RGCs and its localization is not affected by optic nerve injury, suggesting that HDAC5 does not directly suppress regenerative associated genes in these cells. Manipulation of the PKCμ pathway, the canonical pathway that regulates HDAC5 localization in PNS neurons by phosphorylating serine 259 and 498, and other pathways that regulate nuclear/cytoplasmic transport, did not affect HDAC5 cytoplasmic localization in RGC. Also, an HDAC5 mutant whose serine 259 and 488 were replaced by alanine (HDAC5^AA) to prevent phosphorylation and nuclear export showed a predominantly cytoplasmic localization, suggesting that HDAC5 resides mostly in the cytoplasm in RGCs. Interestingly, expression of HDAC5^AA, but not HDAC5 wild type, in RGCs in vivo promoted optic nerve regeneration and RGC survival. Mechanistically, we found that HDAC5^AA stimulated the survival and regeneration of RGCs by activating the mTOR pathway. Consistently, the combination of HDAC5^AA expression and the stimulation of the immune system by zymosan injection had an additive effect in promoting robust axon regeneration. These results reveal the potential of manipulating HDAC5 phosphorylation state to activate the mTOR pathway, offering a new therapeutic target to design drugs that promote axon regeneration in the optic nerve.