O-GlcNAc signaling increases neuron regeneration through one-carbon metabolism in Caenorhabditis elegans
Curation statements for this article:-
Curated by eLife
eLife assessment
This important work reveals that increased flux towards one carbon metabolism improves neuronal regeneration after injury in C. elegans. The presented data are solid and provide compelling support for this conclusion. The manuscript can still be improved in order to strengthen some of the specific conclusions made and to increase the clarity of the presentation.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
Abstract
Cellular metabolism plays an essential role in the regrowth and regeneration of a neuron following physical injury. Yet, our knowledge of the specific metabolic pathways that are beneficial to neuron regeneration remains sparse. Previously, we have shown that modulation of O-linked β-N-acetylglucosamine (O-GlcNAc) signaling, a ubiquitous post-translational modification that acts as a cellular nutrient sensor, can significantly enhance in vivo neuron regeneration. Here, we define the specific metabolic pathway by which O-GlcNAc transferase ( ogt-1 ) loss of function mediates increased regenerative outgrowth. Performing in vivo laser axotomy and measuring subsequent regeneration of individual neurons in C. elegans , we find that glycolysis, serine synthesis pathway (SSP), one-carbon metabolism (OCM), and the downstream transsulfuration metabolic pathway (TSP) are all essential in this process. The regenerative effects of ogt-1 mutation are abrogated by genetic and/or pharmacological disruption of OCM and the SSP linking OCM to glycolysis. Testing downstream branches of this pathway, we find that enhanced regeneration is dependent only on the vitamin B12 independent shunt pathway. These results are further supported by RNA sequencing that reveals dramatic transcriptional changes by the ogt-1 mutation, in the genes involved in glycolysis, OCM, TSP, and ATP metabolism. Strikingly, the beneficial effects of the ogt-1 mutation can be recapitulated by simple metabolic supplementation of the OCM metabolite methionine in wild-type animals. Taken together, these data unearth the metabolic pathways involved in the increased regenerative capacity of a damaged neuron in ogt-1 animals and highlight the therapeutic possibilities of OCM and its related pathways in the treatment of neuronal injury.
Article activity feed
-
-
eLife assessment
This important work reveals that increased flux towards one carbon metabolism improves neuronal regeneration after injury in C. elegans. The presented data are solid and provide compelling support for this conclusion. The manuscript can still be improved in order to strengthen some of the specific conclusions made and to increase the clarity of the presentation.
-
Reviewer #1 (Public Review):
In this manuscript, Yadav and colleagues explore the metabolic changes associated with the regeneration of mechanosensory neurons in O-GlcNAc transferase (ogt-1) mutant worms. Using in vivo laser axotomy to assess the regeneration of individual mechanosensory neurons in C elegans, the authors discovered increased regeneration in ogt-1 mutant worms diverts enhanced glycolysis towards one-carbon metabolism and the downstream transsulfuration metabolic pathway. By genetically and pharmacologically disrupting one-carbon metabolism, they were able to abrogate this phenotype. Similar results were obtained by targeting the serine synthesis pathway. Furthermore, the authors tested downstream targets of this pathway and discovered that the vitamin B12 independent shunt pathway confers regeneration competence in these …
Reviewer #1 (Public Review):
In this manuscript, Yadav and colleagues explore the metabolic changes associated with the regeneration of mechanosensory neurons in O-GlcNAc transferase (ogt-1) mutant worms. Using in vivo laser axotomy to assess the regeneration of individual mechanosensory neurons in C elegans, the authors discovered increased regeneration in ogt-1 mutant worms diverts enhanced glycolysis towards one-carbon metabolism and the downstream transsulfuration metabolic pathway. By genetically and pharmacologically disrupting one-carbon metabolism, they were able to abrogate this phenotype. Similar results were obtained by targeting the serine synthesis pathway. Furthermore, the authors tested downstream targets of this pathway and discovered that the vitamin B12 independent shunt pathway confers regeneration competence in these neurons. They also included RNA-Seq data to support the same conclusion. Ogt-1 mutants showed profound transcriptional changes in genes related to glycolysis and one-carbon metabolism. Perhaps more excitingly, supplementation of the methioninine in wild-type worms is sufficient to recapitulate the regenerative phenotype found in ogt-1 mutants.
I found these results convincing and novel. The experimental approach is elegant and the conclusions are robust. The supplemental data support the major points of the paper. The identification of specific metabolic pathways associated with axon growth and regeneration represents a significant contribution to the Neuroscience field. Interrogation of these data sets and pathways will certainly spark new exciting research in the years to come.
-
Reviewer #2 (Public Review):
This is a potentially important finding regarding the roles of O-GlcNAc cycling and one-carbon metabolism in nerve regeneration. In a previous paper (Taub et al. 2018) they showed that both ogt-1 and oga-1 mutants show strong activation of a neuronal regeneration phenotype. However, the different biological processes used for the neural regeneration phenotype differed between the ogt-1 and oga-1 mutants. Several small issues emerge in the present paper which will increase the interest in the findings presented.
In summary, this paper under review is a potentially important finding which upon further documentation will be an excellent contribution.
-
