Abstract
Parkinson’s disease (PD) is an irreversible and progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta. Growing evidence indicates that endoplasmic reticulum stress is a hallmark of PD; however, its exact contribution to the disease process remains poorly understood. Here, we used molecular biology methods and RNA-Seq analysis to explored an unexpected role of spliced X-Box binding protein 1 (XBP1s) in the nervous system. In this study, we determined that the IRE1α/XBP1 pathway is activated in MPP+-treated neurons. Furthermore, XBP1s was identified as a substrate of CDK5 and that the phosphorylation of XBP1s at the Ser61 residue enhances its nuclear migration, whereas mutation of the residue to alanine substantially reduces its nuclear translocation and activity. Importantly, phosphorylated XBP1s acts as a nuclear transcription factor for multiple target genes, including metabolic-related genes, FosB, and non-coding RNAs. Our findings confirm that the IRE1α/XBP1 pathway is activated in PD, and reveal a novel role of XBP1s in the pathogenesis of PD. This pathway may be a new therapeutic strategy for PD.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by specific motor symptoms such as resting tremor, rigidity, bradykinesia, hypokinesia, and akinesia, affecting 1% of the population over 60 years of age[1]
XBP1s mRNA was significantly increased after 6 h and peaked after approximately 12 h (Fig. 1A) in primary cortical neurons exposed to MPP+21
Primary cultured neurons treated with rotenone, another neurotoxicity in dopaminergic neurons for experimental models of PD22, showed a higher translocation of XBP1s to the nucleus (Supplementary Fig. S2A and B), and the nuclear translocation of XBP1s reduced after pretreating with Ros (Supplementary Fig. S2C and D)
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by specific motor symptoms such as resting tremor, rigidity, bradykinesia, hypokinesia, and akinesia, affecting 1% of the population over 60 years of age[1]. Cortical neurons incubated with MPP+ (100 μM) showed a higher translocation of XBP1s to the nucleus over time (Fig. 1D and E). Our data showed that the IRE1α/XBP1 pathway was activated, which was independent on CDK5, and the increased translocation of XBP1s was dependent on CDK5 but not p38 MAPK in MPP+-treated neurons.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
