EndothelialFAM171A2isrequiredformaintainingautophagyfluxandblood–brainbarrierintegrity

EndothelialFAM171A2isrequiredformaintainingautophagyfluxandblood–brainbarrierintegrity

Si-DaHana,d,1,NingDingb,1,Jia-huiHuangb,Yi-WeiFenga,Kai-MinWua,Shi-DongChena,QiangDonga,MeiCuia,Ting-tingWangc,⁎,PengYuanb,⁎,Jin-TaiYua,⁎aDepartmentofNeurology,HuashanHospital,StateKeyLaboratoryofMedicalNeurobiologyandMOEFrontiersCenterforBrainScience,FudanUniversity,Shanghai200040,ChinabDepartmentofRehabilitationMedicine,HuashanHospital,StateKeyLaboratoryofMedicalNeurobiology,InstituteforTranslationalBrainResearch,MOEFrontiersCenterforBrainScience,MOEInnovativeCenterforNewDrugDevelopmentofImmuneInflammatoryDiseases,FudanUniversity,Shanghai200032,ChinacDepartmentofPharmacy,HuashanHospital,FudanUniversity,Shanghai200040,ChinadDepartmentofNeurology,ShanghaiGeneralHospital,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai200080,China

Abstract

Previous studies linked FAM171A2 to neurodegenerative diseases and suggested its suppression as a therapeutic target. Cerebral endothelial cells also show high expression of FAM171A2, yet the functions remain undefined. We found that endothelial FAM171A2 localizes on vesicular structures, including endosomes, autophagosomes, and lysosomes. In vitro studies using endothelial cells from wild-type and Fam171a2 knockout mice revealed that Fam171a2 deficiency disrupts autophagic flux. Analysis from isolated vesicles showed that Fam171a2 deficiency reduces the assembly of the SNARE complex, suggesting impaired autophagosome-lysosome fusion. This disruption was associated with increased endothelial apoptosis. Overexpression of a SNARE complex component, STX17, reversed autophagosome dysfunction and apoptosis due to Fam171a2 deficiency. In vivo two-photon imaging demonstrated that endothelial-specific deletion of Fam171a2 causes blood–brain barrier leakage, accompanied with astrogliosis. Together, these findings identify FAM171A2 as a regulator of autophagosome–lysosome fusion in endothelial cells and caution against unspecific suppression of FAM171A2 as a potential intervention of neurodegenerative diseases.