Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
JCI Insight. 2018 Aug 23;3(16). doi: 10.1172/jci.insight.99007.
AEP is an age-dependent lysosomal asparaginyl endopeptidase that cleaves numerous substrates including tau and α-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 α-synuclein. Remarkably, the unphosphorylated T322A mutant increases tau or α-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 α-SNCA mice elicits α-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.
AEP 是一种依赖年龄的溶酶体天冬酰胺内肽酶，可切割包括 tau 和 α-synuclein 在内的多种底物，并介导它们在神经退行性疾病中的病理作用。然而，调节这种关键蛋白酶的分子机制仍不完全清楚。在这里，我们表明脑源性神经营养因子 (BDNF) 处理会使 Akt 在 AEP 的 T322 残基上磷酸化，并触发其溶酶体易位和失活。当神经退行性疾病中 BDNF 水平降低时，AEP T322 磷酸化会减弱。因此，AEP 被激活并易位到细胞质中，在细胞质中它会切割 tau 和 α-synuclein。值得注意的是，未磷酸化的 T322A 突变体增加了 AEP 对 tau 或 α-synuclein 的切割，并增强了细胞死亡，而磷酸化模拟 T322E 突变体抑制了这些效应。有趣的是，将 T322E 病毒注入 Tau P301S 小鼠中可拮抗 tau N368 的切割和 tau 病理学，挽救突触功能障碍和认知缺陷。相比之下，将 T322A 病毒注入年轻的 α-SNCA 小鼠中会引发 α-synuclein N103 的切割，并促进多巴胺能神经元丢失，从而促进运动缺陷。因此，我们的发现支持这样一种观点，即 BDNF 通过 Akt 磷酸化抑制 AEP 来促进神经退行性疾病的发病机制。
