The Regulation Mechanism Of RNA Alternative Splicing Of Genes Related To Neurogenetic Diseases And Cognitive Disorders

RNA alternative splicing(AS)is the key mechanism to generate vast transcriptomic and proteomic complexity,which is widespread in the nervous system.Recent publications demonstrate that AS misregulations have been linked to human neurodegenerative and cognitive diseases such as Alzheimers disease(AD),amyotrophic lateral sclerosis(ALS),myotonic dystrophy(DM)and autism(ASD).However,which of the numerous AS events lead to the pathogenesis of those diseases is still not fully understood.It is of great significance to understand the molecular mechanism of human neurological disorders and diseases by systematically exploring the functions of splice variants in disease contexts.To explore the relationship between RNA alternative splicing and neurological pathogenesis,we carried out two studies.One is to characterize the role of RNA splicing factor HNRNPA1 in neurodegenerative diseases.In our study,we revealed that RNA splicing factor HNRNPA1 is a new pathogenic factor of myotonic dystrophy type 1(DM1).Its role is similar to CELF1(the known DM1 pathogenic factor)to promote fetal splicing in DM1.The expression level of HNRNPA1 is gradually down-regulated during normal development,but significantly up-regulated in DM1 patients,where it also promotes a splicing shift of DM1-related RNAs to fetal patterns.Furthermore,CELF1 and HNRNPA1 have different DM1 targets in muscle cells.Our study suggests that DM1 spliceopathy results from the comisregulation of multiple RNA splicing factors.Another study is to explore the mechanism and physiological significance of alternative splicing of ASD susceptible genes,Neurexins(Nrxns).Neurexins are presynaptic cell-adhesion molecules recognized as key organizers of synapses that are essential for synaptic assembly and plasticity.The regulation mechanisms of ?-neurexins alternative splicing are rearly studied,especially for non-AS4 splicing sites.Here,we discovered a neuronal-specific splicing factor nSR100/SRRM4 and its homolgue SRRM3 able to regulate the AS of Nrxns AS3 and AS6 microexons.Furthermore,the AS of these Nrxns microexons are neuronal activity dependent.And the AS of the microexon,AS6,is neuronal-specific.Alternative splicing of AS3 and AS6 can affect the dynamic postsynaptic clustering of PSD95 and Gephyrin,which suggest the potential roles of these microexons in maintaining inhibitory and excitatory synaptic balance as well.However,the potential physiological functions of Nrxns microexon AS associated with the higher neural behaviors still needs further elucidation.