Fig. 1

The regulation of δ-secretase in neurodegenerative diseases. The expression of δ-secretase is regulated by the transcriptional factor C/EBPβ, which is regulated by the BDNF/TrkB signalling pathway. δ-secretase is phosphorylated by Akt which inhibits its activity, and SRPK2 which enhances its activity. δ-secretase also cleaves α-synuclein, generating α-synuclein (1–103) fragment and promotes the onset of PD. Furthermore, α-synuclein (1–103) fragment activates MAO-B, which catalyses the oxidative deamination of dopamine and generation of DOPEL. DOPEL further activates δ-secretase. δ-secretase also cleaves TDP-43, which is indicated in FTD/ALS. δ-secretase cleaves APP, promoting the generation of Aβ. δ-secretase also cleaves tau, generating an aggregation-prone fragment. δ-secretase-derived tau fragment enhances BACE1 activity, which further facilitate Aβ production. δ-secretase-derived SET fragments inhibit the dephosphorylation of tau, while δ-secretase-derived SRPK2 fragment affects the alternative splicing of tau. All these pathways promote tau aggregation and the onset of AD