Menin Mediates Tat-induced Neuronal Apoptosis In Tat-Treated Cells And In Brain Frontal Cortex Of SIV-infected Macaques

Neuronal apoptosis is the main pathological feature in human immunodeficiency virus(HIV)-associated neurocognitive disorder(HAND).Neuronal apoptosis is associated with HIV-1 transactivator of transcription(Tat)protein,but the mechanism of apoptosis remains poorly unclear.Recent studies suggested that the transactivation of HIV-1 Tat required multiple endocrine neoplasia type 1(MEN1)tumor suppressor protein menin,suggesting that menin may be involved in Tat-induced neuronal damage.Here,we used western blot,TUNEL,qRT-PCR,double immunohistochemical staining and other experimental methods to determine the detailed role of menin in mediating HIV-1 Tat-induced neuronal apoptosis,using a combination of multiple models systems including cell-based research and SIV infected macaque model.Cell-based research found that Tat could induced neuronal apoptosis and up-regulation menin in pRK5M-tat-flag-transfected SY5Y cells and recombinant Tat-treated mouse embryonic neurons.Moreover,overexpression of menin showed that it can induce SY5Y cell apoptosis.Further studies showed that knockdown of menin by pll3.7-MEN 1-shRNA attenuated the Tat-induced cleavage of caspase-3 and caspase-8 in SY5Y cells.In addition,we found that menin expression was increased in the neurons of the frontal cortex with SIV-infected macaques,more importantly,the number of menin-staining cells was positively correlated with cells shown caspase-3 activation while it was negatively correlated with NeuN-positive cells.Together,our results revealed that menin mediated Tat-induced neuronal apoptosis,and indicating that targeting menin may be potential to block Tat-induced neuronal apoptosis.Our study provides a new and effective molecular target for the treatment of HAND.