| First Author | Wang ZH | Year | 2018 |
| Journal | JCI Insight | Volume | 3 |
| Issue | 16 | PubMed ID | 30135302 |
| Mgi Jnum | J:315628 | Mgi Id | MGI:6829433 |
| Doi | 10.1172/jci.insight.99007 | Citation | Wang ZH, et al. (2018) BDNF inhibits neurodegenerative disease-associated asparaginyl endopeptidase activity via phosphorylation by AKT. JCI Insight 3(16) |
| abstractText | 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. |
