The Role of Deimination in Regenerative Reprogramming of Neurons

Abstract

Neurons from the adult central nervous system (CNS) demonstrate limited mRNA transport and localized protein synthesis versus developing neurons, correlating with lower regenerative capacity. We found that deimination (posttranslational conversion of protein-bound arginine into citrulline) undergoes upregulation during early neuronal development while declining to a low basal level in adults. This modification is associated with neuronal arborization from amphibians to mammals. The mRNA-binding proteins (ANP32a, REF), deiminated in neurons, have been implicated in local protein synthesis. Overexpression of the deiminating cytosolic enzyme peptidyl arginine deiminase 2 in nervous systems results in increased neuronal transport and neurite outgrowth. We further demonstrate that enriching deiminated proteins rescues transport deficiencies both in primary neurons and mouse optic nerve even in the presence of pharmacological transport blockers. We conclude that deimination promotes neuronal outgrowth via enhanced transport and local protein synthesis and represents a new avenue for neuronal regeneration in the adult CNS.

Lyso-Lipid-Induced Oligodendrocyte Maturation Underlies Restoration of Optic Nerve Function

“…Immunoprecipitation methods were adapted from our previous study ( Ding et al, 2019 ). Lysates prepared from bacteria were subjected to immunoprecipitation using an antibody for MPB (catalog #ab7349, Abcam).…”

In vivo expression of peptidylarginine deiminase in Drosophila melanogaster

“…In a transgenic mammalian model, the introduction of 30 copies of PAD2 cDNA in myelin sheath led to spontaneous signs of demyelination in the central nervous system, which is a hallmark of multiple sclerosis [34]. Interestingly, PAD2 overexpression in mouse retina resulted in increased facilitated neuronal transport and visual function restoration [35]. Previous work also showed that PAD2 overexpression in transgenic mice models led to spontaneous skin neoplasia formation as well as increased malignancy and tumor-related inflammation of chemically-induced tumors [36,37].…”