Small heterodimer partner (SHP) aggravates ER stress in Parkinson's disease-linked LRRK2 mutant astrocyte by regulating XBP1 SUMOylation.

backgroundEndoplasmic reticulum (ER) stress is a common feature of Parkinson's disease (PD), and several PD-related genes are responsible for ER dysfunction. Recent studies suggested LRRK2-G2019S, a pathogenic mutation in the PD-associated gene LRRK2, cause ER dysfunction, and could thereby contribute to the development of PD. It remains unclear, however, how mutant LRRK2 influence ER stress to control cellular outcome. In this study, we identified the mechanism by which LRRK2-G2019S accelerates ER stress and cell death in astrocytes.

methodsTo investigate changes in ER stress response genes, we treated LRRK2-wild type and LRRK2-G2019S astrocytes with tunicamycin, an ER stress-inducing agent, and performed gene expression profiling with microarrays. The XBP1 SUMOylation and PIAS1 ubiquitination were performed using immunoprecipitation assay. The effect of astrocyte to neuronal survival were assessed by astrocytes-neuron coculture and slice culture systems. To provide in vivo proof-of-concept of our approach, we measured ER stress response in mouse brain.

resultsMicroarray gene expression profiling revealed that LRRK2-G2019S decreased signaling through XBP1, a key transcription factor of the ER stress response, while increasing the apoptotic ER stress response typified by PERK signaling. In LRRK2-G2019S astrocytes, the transcriptional activity of XBP1 was decreased by PIAS1-mediated SUMOylation. Intriguingly, LRRK2-GS stabilized PIAS1 by increasing the level of small heterodimer partner (SHP), a negative regulator of PIAS1 degradation, thereby promoting XBP1 SUMOylation. When SHP was depleted, XBP1 SUMOylation and cell death were reduced. In addition, we identified agents that can disrupt SHP-mediated XBP1 SUMOylation and may therefore have therapeutic activity in PD caused by the LRRK2-G2019S mutation.

conclusionOur findings reveal a novel regulatory mechanism involving XBP1 in LRRK2-G2019S mutant astrocytes, and highlight the importance of the SHP/PIAS1/XBP1 axis in PD models. These findings provide important insight into the basis of the correlation between mutant LRRK2 and pathophysiological ER stress in PD, and suggest a plausible model that explains this connection.