Study On The Interplay Among TMEM59,TREM2 And DAP12

Alzheimer's disease(AD)is the most common type of dementia,which is mainly characterized by memory impairment.The pathological features of AD include senile plaques composed of P-amyloid peptides,neurofibrillary tangles formed by hyperphosphorylated tau proteins,and neuronal loss.The autophagy-related single transmembrane protein TMEM59 has been found to be associated with AD,but the underlying mechanism remains elusive.Our group has recently found that TMEM59 can interact with TREM2,a transmembrane protein associated with AD.TREM2 can interact with the adaptor protein DAP 12 through TREM2-K186 and DAP12-D50 sites,to activate downstream signaling pathways for inflammatory responses and phygocytosis in microglia.In this study,we further demonstrate that TMEM59 can interact with both TREM2 and DAP 12 through its transmembrane domain.However,mutations of TREM2-K186 and DAP12-D50 sites have no effect on their interactions with TMEM59.We find that TMEM59 and the cleaved TREM2 carboxyl-terminal fragment were degraded through both the proteasome and the lysosome pathways,whereas DAP 12 is degraded only through the proteasome pathway.Interestingly,overexpression of TREM2 can reduce TMEM59 protein levels through promoting TMEM59 degradation,but not vice versa.Overexpression of TMEM59 can reduce DAP 12 protein levels,but not vice versa.Treatments with LPS reduce both TREM2 and TMEM59 gene expression in a similar manner.Moreover,overexpression of TMEM59 in BV2 cells has no effect on protein levels of the transcription factor NF-?B and its downstream signaling factors,or factors related to autophagy.In summary,our study demonstate that TREM2 can regulate TMEM59 protein levels and that TMEM59 can regulate DAP 12 protein levels;and this suggests that TMEM59 migh play a modulatory role in the TREM2-DAP12 signaling,shedding new lights on understanding the molecular pathogenesis mechanism for AD.