Discovery of a molecular glue that enhances UPR^mtto restore proteostasis<i>via</i>TRKA-GRB2-EVI1-CRLS1 axis

<jats:title>Abstract</jats:title><jats:p>Lowering proteotoxicity is a potentially powerful approach for the treatment of neurological disorders, such as Parkinson’s disease. The unfolded protein response (UPR) is a major mechanism that preserves the network maintaining cellular proteostasis. In the present study, we developed the screening strategy to discover compounds that significantly enhanced the activation of mitochondrial UPR (UPR<jats:sup>mt</jats:sup>) through increasing cardiolipin content. We identified that ginsenoside Rg3 (Rg3) increased cardiolipin depending on cardiolipin synthase 1 (CRLS1) in both worms and in human neural cells. Using LiP-SMap (limited proteolysis-mass spectrometry) strategy, we identified GRB2 (growth factor receptor bound protein 2) as a direct target of Rg3 in human neural cells. Rg3 enhances the binding between GRB2 and TRKA, that transduces signals<jats:italic>via</jats:italic>phosphrorylation of ERK. We provide bioinformatic and experimental evidence that EVI1, the critical oncogenic transcriptional regulator in leukemia, binds to<jats:italic>CRLS1</jats:italic>promoter region and stimulated<jats:italic>CRLS1</jats:italic>expression and subsequently increased cardiolipin content in the presence of Rg3. In a Parkinson’s disease mouse model, Rg3 restores motor function by protecting nigral dopaminergic neurons dependent on Grb2. Our data recapitulate the TRKA-GRB2-EVI1-CRLS1 axis in maintaining proteostasis in Parkinson’s disease<jats:italic>via</jats:italic>UPR<jats:sup>mt</jats:sup>.</jats:p>