The Endoplasmic Reticulum Chaperone GRP78/BiP Modulates Prion Propagation in vitro and in vivo.
Prion diseases are fatal neurodegenerative disorders affecting several mammalian species, characterized by the accumulation of the misfolded form of the prion protein, which is followed by the induction of endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR). GRP78, also called BiP, is a master regulator of the UPR, reducing ER stress levels and apoptosis due to an enhancement of the cellular folding capacity. Here, we studied the role of GRP78 in prion diseases using several in vivo and in vitro approaches. Our results show that a reduction in the expression of this molecular chaperone accelerates prion pathogenesis in vivo. In addition, we observed that prion replication in cell culture was inversely related to the levels of expression of GRP78 and that both proteins interact in the cellular context. Finally, incubation of PrPScwith recombinant GRP78 led to the dose-dependent reduction of protease-resistant PrPScin vitro. Our results uncover a novel role of GRP78 in reducing prion pathogenesis, suggesting that modulating its levels/activity may offer a novel opportunity for designing therapeutic approaches for these diseases. These findings may also have implications for other diseases involving the accumulation of misfolded proteins.
Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030, USA.
Kyung-Won
KW
Park
Department of Obstetrics and Gynecology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Gyoung
G
Eun Kim
Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030, USA.
Rodrigo
R
Morales
Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030, USA.
Fabio
F
Moda
Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030, USA.
Ines
I
Moreno-Gonzalez
Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030, USA.|Universidad de los Andes, Facultad de Medicina. Av San Carlos de Apoquindo 2200, Las Condes, Santiago, Chile.
Luis
L
Concha-Marambio
Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, USA.
Amy S
AS
Lee
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.|Center for Geroscience, Brain Health and Metabolism, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.|Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston MA, USA.|Buck Institute for Research on Aging, Novato, CA, 94945, USA.
Claudio
C
Hetz
Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Houston Medical School, 6431 Fannin St, Houston, TX 77030, USA.|Universidad de los Andes, Facultad de Medicina. Av San Carlos de Apoquindo 2200, Las Condes, Santiago, Chile.
Claudio
C
Soto
D000818:Animals; D002460:Cell Line; D002474:Cell-Free System; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000378:metabolism; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D011485:Protein Binding; D014617:Vacuoles / Q000378:metabolism
D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018620:PrPSc Proteins; D011328:Prions; D010447:Peptide Hydrolases