Abstract
Neurodegenerative diseases are often associated with dysfunction in protein quality control. The endoplasmic reticulum (ER), a key site for protein synthesis, senses stressful conditions by activating the unfolded protein response (UPR). In this study we report the creation of a novel mouse model in which GRP78/BiP, a major ER chaperone and master regulator of UPR, is specifically eliminated in Purkinje cells (PCs). GRP78-depleted PCs activate UPR including the induction of GRP94, PDI, CHOP and GADD34, feedback suppression of eIF2α phosphorylation and apoptotic cell death. In contrast to current models of protein misfolding in which an abnormal accumulation of ubiquitinated protein is prominent, cytosolic ubiquitin staining is dramatically reduced in GRP78-null PCs. Ultrastructural evaluation reveals that the ER shows prominent dilatation with focal accumulation of electron-dense material within the ER. The mice show retarded growth and severe motor coordination defect by week 5 and cerebellar atrophy by week 13. Our studies uncover a novel link between GRP78 depletion and reduction in cytosolic ubiquitination and establish a novel mouse model of accelerated cerebellar degeneration with basic and clinical applications.
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Abbreviations
- ER:
-
endoplasmic reticulum
- ERAD:
-
ER-associated protein degradation
- PCs:
-
Purkinje cells
- UPR:
-
unfolded protein response
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Acknowledgements
We thank Dr. Robert Maxson and the Lee laboratory members for helpful discussion. We thank the University of Southern California/Norris Comprehensive Cancer Center Transgenic Core Facility, the Cell and Tissue Imaging Core Facility, the Translational Pathology Core Facility and the Biostatistics Core Facility for assistance and consultation. This work was supported by the NIH Grants R01-CA027607, R01-CA111700 and the Freeman Cosmetic Chair to ASL.
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Supplementary Information accompanies the paper on Cell Death and Differentiation website (http://www.nature.com/cdd)
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Wang, M., Ye, R., Barron, E. et al. Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis. Cell Death Differ 17, 488–498 (2010). https://doi.org/10.1038/cdd.2009.144
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DOI: https://doi.org/10.1038/cdd.2009.144
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