HOTTIP downregulation reduces neuronal damage and microglial activation in Parkinson's disease cell and mouse models

摘要

HOXA transcript at the distal tip(HOTTIP),a newly identified long noncoding RNA,has been shown to exhibit anti-inflammatory effects and inhibit oxygen-glucose deprivation-induced neuronal apoptosis.However,its role in Parkinson's disease(PD)remains unclear.1-Methyl-4-phenylpyridium(MPP+)and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)were used to establish PD models in SH-SY5 Y and BV2 cells and in C57 BL/6 male mice,respectively.In vitro,after HOTTIP knockdown by sh-HOTTIP transfection,HOTTIP and FOXO1 overexpression promoted SH-SY5 Y apoptosis,BV2 microglial activation,proinflammatory cytokine expression,and nuclear factor kappa-B and NACHT,LRR and PYD domains-containing protein 3 inflammasome activation.Overexpression of mi R-615-3 p inhibited MPP+-induced neuronal apoptosis and microglial inflammation and ameliorated HOTTIP-and FOXO1-mediated nerve injury and inflammation.In vivo,HOTTIP knockdown alleviated motor dysfunction in PD mice and reduced neuronal apoptosis and microglial activation in the substantia nigra.These findings suggest that inhibition of HOTTIP mitigates neuronal apoptosis and microglial activation in PD models by modulating mi R-615-3 p/FOXO1.This study was approved by the Ethics Review Committee of the Affiliated Hospital of Qingdao University,China(approval No.UDX-2018-042)in June 2018.