Fig. 3

Molecular targets in the modulation of protein translation initiation implicated in proteostasis and PD pathogenesis and therapy Ribosomal protein biogenesis can be exquisitely modulated on multiple targets mainly through the modulation of functions of protein targets via phosphorylation and dephosphorylation by kinases and phosphatases, respectively. Multiple factors including eIF4G1, eIF4E, eIF4A, eIF3, eIF5, and eIF2 take part in the formation of the translation initiation complex, which is vital for initiation of protein translation. The kinase-induced phosphorylation of eIF4E, 4E-BP1, RPS15 and RPS6 will facilitate protein translation, which is supposed to be adverse to the maintenance of proteostasis under stress and implicated in PD pathogenesis. Mnk1 can phosphorylate eIF4E to enhance its binding with eIF4G1 to promote translation initiation, which can be abrogated by eIF4G2 chelation. However, the function of eIF4E can be inhibited by 4E-BP1 sequestration, which can be abrogated by LRRK2 and mTORC1 kinase-induced 4E-BP1 phosphorylation. LRRK2 kinase can also phosphorylate RPS15 to enhance protein translation, whereas mTORC1 kinase can phosphorylate S6K1. The phosphorylated S6K1 subsequently phosphorylates RPS6, which in turn promotes protein translation. LRRK2 and mTORC1 kinase inhibitors are supposed to have potential therapeutic effects against neurodegeneration in PD. On the other hand, the phosphorylation of eIF2α by PERK kinases can inhibit protein biogenesis. However, GADD34 can direct PP1 to dephosphorylate eIF2α, which can restore protein translation. GBZ can block GADD34 to promote eIF2α phosphorylation and arrest protein translation, whereas GSK2606414 can inhibit kinase-induced eIF2α phosphorylation to recover protein biogenesis. ISRIB, Trazodone and DBM can function downstream of eIF2α phosphorylation without influence on eIF2α phosphorylation to promote protein translation. However, all three FDA-approved drugs (GBZ, Trazodone and DBM) claim to have protective capacities against neurodegeneration in PD