PMID- 30135302 OWN - NLM STAT- MEDLINE DCOM- 20191210 LR - 20220408 IS - 2379-3708 (Electronic) IS - 2379-3708 (Linking) VI - 3 IP - 16 DP - 2018 Aug 23 TI - BDNF inhibits neurodegenerative disease-associated asparaginyl endopeptidase activity via phosphorylation by AKT. LID - 99007 [pii] LID - 10.1172/jci.insight.99007 [doi] LID - e99007 AB - AEP is an age-dependent lysosomal asparaginyl endopeptidase that cleaves numerous substrates including tau and alpha-synuclein and mediates their pathological roles in neurodegenerative diseases. However, the molecular mechanism regulating this critical protease remains incompletely understood. Here, we show that Akt phosphorylates AEP on residue T322 upon brain-derived neurotrophic factor (BDNF) treatment and triggers its lysosomal translocation and inactivation. When BDNF levels are reduced in neurodegenerative diseases, AEP T322 phosphorylation is attenuated. Consequently, AEP is activated and translocates into the cytoplasm, where it cleaves both tau and alpha-synuclein. Remarkably, the unphosphorylated T322A mutant increases tau or alpha-synuclein cleavage by AEP and augments cell death, whereas phosphorylation mimetic T322E mutant represses these effects. Interestingly, viral injection of T322E into Tau P301S mice antagonizes tau N368 cleavage and tau pathologies, rescuing synaptic dysfunction and cognitive deficits. By contrast, viral administration of T322A into young alpha-SNCA mice elicits alpha-synuclein N103 cleavage and promotes dopaminergic neuronal loss, facilitating motor defects. Therefore, our findings support the notion that BDNF contributes to the pathogenesis of neurodegenerative diseases by suppressing AEP via Akt phosphorylation. FAU - Wang, Zhi-Hao AU - Wang ZH AD - Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA. AD - Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Wu, Wanqiang AU - Wu W AD - Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA. AD - Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, China. FAU - Kang, Seong Su AU - Kang SS AD - Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA. FAU - Liu, Xia AU - Liu X AD - Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA. FAU - Wu, Zhiping AU - Wu Z AD - Departments of Structural Biology and Developmental Neurobiology, St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. FAU - Peng, Junmin AU - Peng J AD - Departments of Structural Biology and Developmental Neurobiology, St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. FAU - Yu, Shan Ping AU - Yu SP AD - Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia, USA. FAU - Manfredsson, Fredric P AU - Manfredsson FP AD - Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USA. FAU - Sandoval, Ivette M AU - Sandoval IM AD - Department of Translational Science & Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USA. FAU - Liu, Xuebo AU - Liu X AD - Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, China. FAU - Wang, Jian-Zhi AU - Wang JZ AD - Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Ye, Keqiang AU - Ye K AD - Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA. LA - eng GR - R01 AG047928/AG/NIA NIH HHS/United States GR - RF1 AG051538/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180823 PL - United States TA - JCI Insight JT - JCI insight JID - 101676073 RN - 0 (Bdnf protein, mouse) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Recombinant Proteins) RN - 0 (alpha-Synuclein) RN - 0 (tau Proteins) RN - 7171WSG8A2 (BDNF protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.4.22.- (Cysteine Endopeptidases) RN - EC 3.4.22.34 (asparaginylendopeptidase) SB - IM MH - Animals MH - Brain/cytology/metabolism/pathology MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Cell Line, Tumor MH - Cysteine Endopeptidases/genetics/*metabolism MH - Disease Models, Animal MH - HEK293 Cells MH - Humans MH - Lysosomes/metabolism MH - Mice MH - Mice, Knockout MH - Mutation MH - Neurodegenerative Diseases/*pathology MH - Neurofibrillary Tangles/metabolism/pathology MH - Neurons MH - Phosphorylation/genetics MH - Primary Cell Culture MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Rats MH - Recombinant Proteins/genetics/metabolism MH - alpha-Synuclein/metabolism MH - tau Proteins/genetics/metabolism PMC - PMC6141178 OTO - NOTNLM OT - Cell Biology OT - Molecular pathology OT - Neurodegeneration OT - Neuroscience COIS- Conflict of interest: The authors have declared that no conflict of interest exists. EDAT- 2018/08/24 06:00 MHDA- 2019/12/18 06:00 PMCR- 2018/08/23 CRDT- 2018/08/24 06:00 PHST- 2017/12/04 00:00 [received] PHST- 2018/07/03 00:00 [accepted] PHST- 2018/08/24 06:00 [pubmed] PHST- 2019/12/18 06:00 [medline] PHST- 2018/08/24 06:00 [entrez] PHST- 2018/08/23 00:00 [pmc-release] AID - 99007 [pii] AID - 10.1172/jci.insight.99007 [doi] PST - epublish SO - JCI Insight. 2018 Aug 23;3(16):e99007. doi: 10.1172/jci.insight.99007. eCollection 2018 Aug 23.