RT Journal Article
SR Electronic
T1 Discovery of a molecular glue that enhances UPR<sup>mt</sup> to restore proteostasis <em>via</em> TRKA-GRB2-EVI1-CRLS1 axis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.17.431525
DO 10.1101/2021.02.17.431525
A1 Qi, Li-Feng-Rong
A1 Qian, Cheng
A1 Liu, Shuai
A1 Peng, Chao
A1 Zhang, Mu
A1 Yang, Peng
A1 Wu, Ping
A1 Li, Ping
A1 Xu, Xiaojun
YR 2021
UL http://biorxiv.org/content/early/2021/02/17/2021.02.17.431525.abstract
AB 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 (UPRmt) 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 via phosphrorylation of ERK. We provide bioinformatic and experimental evidence that EVI1, the critical oncogenic transcriptional regulator in leukemia, binds to CRLS1 promoter region and stimulated CRLS1 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 via UPRmt.Competing Interest StatementThe authors have declared no competing interest.