Functional Characterization Of A Protein Quality Regulator UFD-2 In Axon Regeneration

The protein quality control(PQC)system is responsible for maintaining the homeostasis of the internal environment by stabilizing proteins and degrading misfolded proteins.Axon regeneration is an essential part of the self-repair of the nervous system after axon injury.This process requires a restoration of cellular homeostasis,intensive protein synthesis,and degradation,which pose high pressure on the protein quality control system.Currently,the functions and mechanisms of PQC during axon regeneration is still unclear.Therefore,addressing these key questions will not only help us to understand the molecular mechanism of nerve regeneration,but also lay a theoretical foundation for the treatment of nerve injury.Here,we used a laser injury model to test the functions of PQC regulators in axon regeneration in C.elegans.After a systematic screen using worm mutants,we found that an E3 ubiquitin ligase UFD-2,one of the PQC regulators,inhibits the regeneration of PLM and DD2 neurons.Meanwhile,we found that CEP-1,the nematode homolog of the tumor suppressor p53,also plays an important role in the axonal regeneration of nematode.After axon injury,axon regrowth in ufd-2 deletion mutants was significantly increased.In contrast,cep-1 deletion causes strong inhibition of axon regrowth.Tissue-specific expression of CEP-1 or UFD-2 in neurons or other non-neuronal tissues can rescue the defects caused by deletion mutation,indicating that these two proteins could regulate nerve regeneration through cell-autonomous and cross-tissue mechanisms.Furthermore,genetic dissection by double mutants and rescue experiments suggests that CEP-1 not only partly functions through UFD-2 but also acts as one of its downstream effectors.Through my thesis study,we have unraveled a new axon regeneration pathway through the protein quality control regulator UFD-2 and the transcription factor CEP-1,providing new thoughts for treating spinal cord injury.