Biochemical Investigation Of The Mechanism Of Myelin Breakdown

Myelin sheaths are multilayer membrane structures wrapping around the axons of nerve cells.The functions of myelin sheaths include: 1.To protect the axons;2.To speed up the transduction of action potential by making insulations on the axon;3.To regulate axon regeneration after acute nerve injury.Myelin breakdown happens in demyelinating diseases as well as in nerve injury.In demyelinating diseases,aberrant myelin loss is caused by genetic deficiency,infection or autoimmune responses,resulting in reduced transduction efficiency of action potential and axon degeneration.In response to nerve injury,myelin needs to be cleared in time to facilitate axon regeneration.The exact mechanism of the execution of myelin breakdown is unclear in both cases.Unleashing the mechanism of myelin breakdown is crucial for understanding the pathologic mechanism of demyelinating diseases and the regulation of nerve regeneration.In the current work,we used a model of peripheral sciatic nerve injury to study the mechanism of myelin breakdown.We found that the mixed lineage kinase domain-like protein(MLKL),a protein previously reported to execute necroptosis,executed myelin breakdown following sciatic nerve injury.MLKL expression is induced in Schwann cells after the injury.The rate of myelin breakdown of sciatic nerve in Mlkl knockout mice is significantly slower than in wild-type mice.In the presence of nerve injury signal,MLKL is activated through a phosphorylation event on serine 441,then inserts into myelin sheath membrane via binding with sulfatide,and finally breaks down the myelin.This MLKL mediated myelin breakdown is necessary for axon regeneration.Mlkl knockout mice have a poorer regeneration capability compared with wild-type mice.Overexpression of MLKL in sciatic nerve of wild-type mice can accelerate its functional recovery after injury.There is neither MLKL expression nor myelin breakdown following central optic nerve injury.Ectopic expression of MLKL in injured optic nerve enables it to break down its myelin and to regenerate its axon.In conclusion,our work reported that MLKL regulates myelin breakdown and axon regeneration after nerve injury.The functions of MLKL in this process are achieved through elevated protein expression and phosphorylation modification on its serine 441.Our findings provide new ways for the recovery of injured nerves as well as the treatment of demyelinating diseases.