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- Title
Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis.
- Authors
Wang, M.; Ye, R.; Barron, E.; Baumeister, P.; Mao, C.; Luo, S.; Fu, Y.; Luo, B.; Dubeau, L.; Hinton, D. R.; Lee, A. S.
- 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.
- Subjects
APOPTOSIS; CEREBELLUM degeneration; NEURODEGENERATION; PURKINJE cells; HUMAN heredity
- Publication
Cell Death & Differentiation, 2010, Vol 17, Issue 3, p488
- ISSN
1350-9047
- Publication type
Article
- DOI
10.1038/cdd.2009.144