| Myelin is a unique insulating structure that compactly surrounds the axons of the nervous system.It has pivotal roles in the acceleration of axonal electrical pulses and the metabolic support of neurons.Oligodendrocytes are the myelinating glia in central nervous system,and their damage may lead to demyelinating diseases.ZDHHC5 is a protein acyl transferase that enriches in the brain.It is reported to regulate protein transport in neuronal synapse,but little is known about its function in oligodendrocyte development and myelination.ZDHHC5 is expressed in oligodendrocytes.We conditionally knockout Zdhhc5 in oligodendrocytes by Cre/LoxP recombinase system to evaluate its role in myelination.Zdhhc5cKO mice were born according to Mendel’s Law of Inheritance and have no obvious defect.Immunofluorescent staining shows hypo-myelination in corpus callosum of Zdhhc5cKO mice,accompanied by a reduction in oligodendrocytes.In the LPC-induced demyelination model,Zdhhc5cKO also shows myelin repair retardation after injury.Deletion of ZDHHC5 does not affect the proliferation and differentiation of oligodendrocyte precursor cells(OPCs),but increases the apoptosis level.We identify the transcription factor STAT3 as a palmitoylation substrate of ZDHHC5 by Mass-spectrum screening.Palmitoylation of STAT3 regulates its phosphorylation thus affecting downstream transcription activity that may lead to apoptosis.The palmitoylation-deficient STAT3 induces apoptosis in oligodendrocytes and decrease the expression level of MBP.These data indicate that palmitoylated STAT3 may be an effector in ZDHHC5 deletion-induced hypo-myelination.Our study demonstrates the important role of ZDHHC5 and palmitoylation of STAT3 in oligodendrocyte apoptosis and myelin development,which provides a new insight into the study of demyelination diseases. |
