Protein deacetylases and axonal regeneration

A neuron with injured or severed axon responds with attempts at axonal regrowth. In this regard, axonal regeneration of peripheral nerves occurs far more efficiently compared to central nervous system (CNS) neurons. The latter typically could not form a proper growth cone, and any axonal regeneration in vivo is very limited. The adult CNS environment is not conducive for axonal regrowth. An extensive body of work has revealed mechanisms whereby the myelin-associated inhibitors and extracellular matrix chondroitin sulfate proteoglycans promote collapse of axonal growth cones or repel their advances (Lee and Zheng, 2012). The intrinsic axonal regeneration capacity of an injured neuron is, however, grounded on a combination of factors, including responses to a myriad of survival signaling molecules and pathways, axonal mRNA transport and local protein synthesis, as well as proper axonal growth cone formation and stabilization. Interestingly, recent findings have linked several aspects of axonal regenerative capacity to protein acetylation and deacetylation. Nuclear histone and a myriad of nuclear and cytoplasmic proteins are post-translationally modified by lysine acetylation, mediated by a range of histone acetyltransferases (HATs). Four classes of histone/protein deacetylases could reverse this modification. There are eleven histone deacetylases (HDACs 1–11), which are grouped into classes 1, II and IV (Yang and Seto, 2008). The class III deacetylases, the sirtuin family with seven members in the mammalian system, stands on its own because of their obligatory cofactor dependence on nicotinamide adenine dinucleotide (NAD) (Haigis and Sinclair, 2010). HDACs and sirtuins have a wide range of targets, including histones, transcription factors and cytoplasmic components such as tubulin (Yang and Seto, 2008; Haigis and Sinclair, 2010). In mammals, HDACs and sirtuins-mediated deacetylation are known to have diverse regulatory roles in the nervous system, including cognition and memory. At the cellular level, these deacetylases modulate neuronal activity and survival in a multitude of ways. In principle, protein deacetylases could have direct or indirect role in axonal regeneration. A direct or acute action may pertain to the deacetylases’ regulation of growth cone stabilization through tubulin modification. More indirect and chronic influences by the deacetylases would involve changes in transcriptional and epigenetic profiles that would modulate growth cone formation and axonal outgrowth. Some examples of how HDACs and sirtuins may influence axonal regeneration are highlighted below.