Study On Nuclear Degradation Of Dysbindin,a Schizophrenia Related Protein And Its Regulation Of ERK1/2

Schizophrenia is a disaster mental disease,and has a strong linkage with genetics.It influences about 0.5%-1%population around the world.Up to now,more and more genes are identified and may be involved in schizophrenia pathogenesis.It is vital to explore the related gene function,and we mainly focus on the schizophrenia-related gene DTNBP1.The SNP mutant in DTNBP1 non-coding regions have been linked with schizophrenia in multiple populations.The protein levels and mRNA levels of DTNBP1 are decreased in hippocampal formation of schizophrenia patients,and the mRNA levels are also decreased in cortex of schizophrenia patients.In the dysbindin deficient mice,they show the schizophrenia related behaviors.Thus,the dysbindin has a strong linkage with schizophrenia.Dysbindin-1A localizes mainly in cytoplasm and the dentrites and axon terminal of neuron.Functional studies of dysbindin-1A show it regulate the dopominergic and glutaminergic neurotransmitter systems.Interaction with development related protein,it facilitates the process of neurite outgrowth and synapse formation of neuron.So,dysbindin-1A in sub-cellular location has an important role in executing its function.Otherwise,dysbindin-1A was reported in nucleus to regulate the gene transcription.It may be has a vital role in nucleus,which makes us to understand its function in association with the schizophrenia better.Here,we found that dysbindin-1A is degraded fast in nucleus.The PEST domain on dysbindin-1A may be involved in the process,and dysbindin-1A could regulate synapsin I transcription after entered into nucleus.In addition,dysbindin-1A could interact with ERK1/2,and its location was not altered after the NGF treatment.However,the interaction was reduced between the dysbindin-1A and ERK1/2.The main results are as follows:1.The half-life of dysbindin-1A was short when it entered into nucleus,its ubiquitination was enhanced.Then,it was degraded by the ubiquitin-proteasome system.In human dysbindin-1A,we found three PEST motifs on its C-terminus.The ubiquitination of dysbindin-1A was decreased when the PEST domain was deleted,and its distribution increased in nucleus.However,the half-life after PEST deletion was not increased.2.When we transfected dysbindin-1A with NLS,we observed an increased expression of the synapsin I.3.We found that dysbindin-1A could interact with ERK1/2 while the MEK1 did not.Dysbindin-1A could interact with ERK1/2 directly in vitro and in vivo.Furthermore,the amino acids 42-89 of dysbindin-1A were responsible for the interaction,while the other domains were not.Both regulatory and kinase domains of ERK1/2 could interact with dysbindin-1A.4.After NGF treatment,the localization of dysbindin-1A was not altered apparently.But,the interaction with ERK1/2 was reduced.With the concentration and treated time of NGF different,the interaction between them was reduced lastingly.In summary,the dysbindin-1A could be degraded faster in nucleus and could regulate gene transcription when entered into nucleus.Dysbindin-lA could interact with ERK1/2,and localization of dysbindin-1A was not altered,but the binding ability between them was decreased after NGF treatment.Our data suggest that it may be involved in the neurodevelopment.