Fig. 7

A model showing the regulatory mechanism involving SHP/PIAS1/XBP1 in LRRK2-G2019S mutant astrocytes. In the normal brain, the ER stress activates three UPR sensors, IRE1, PERK and ATF6. One of them, IRE1 activates the transcription factor XBP1 to induce genes that facilitate protein folding and removal of unfolded proteins by ER-associated degradation, including some that encode ER chaperones. However, LRRK2-G2019S negatively regulated XBP1 transcriptional activity by promoting PIAS1-mediated SUMOylation of XBP1, but did not affect phosphorylation and oligomerization of IRE1. LRRK2-G2019S increased expression of SHP, thereby stabilizing the PIAS1 protein. By increasing PIAS1 stability, SHP promotes XBP1 SUMOylation, resulting in failure of adaptive efforts and neuronal death. In this study, we identified doxycycline can disrupt SHP-mediated XBP1 SUMOylation and may therefore have therapeutic activity in PD caused by the LRRK2-GS mutation