The Disulfide Isomerase Grp58 Is a Protective Factor against Prion Neurotoxicity

• DOI: 10.1523/jneurosci.4090-04.2005
• Publication Date: 2005-03-16T20:52:47Z
• Authors: Claudio Hetz; Milene Russelakis...; Sébastien Wälchli; Sonia Carboni; Elisabeth Vial-Kn...; Kinsey Maundrell; Joaquín Castilla; Claudio Soto
• Keywords: Neurotoxicity; Chaperone (clinical)

Prion diseases are transmissible neurodegenerative disorders characterized by extensive neuronal apoptosis and accumulation of misfolded prion protein (PrP SC ). Recent reports indicate that PrP induces via activation the endoplasmic reticulum (ER) stress pathway ER resident caspase-12. Here, we investigate relationship between replication induction during different stages disease in a murine scrapie model. The first alteration observed consists upregulation chaperone glucose-regulated Grp58, which was detected presymptomatic phase followed closely formation . An increase Grp58 expression correlated with at all brain areas, suggesting this may play an important role cellular response to infection. Indeed, vitro studies using N2a neuroblastoma cells demonstrated inhibition small interfering RNA led significant enhancement toxicity. Conversely, overexpression protected against toxicity decreased rate caspase-12 activation. were shown interact coimmunoprecipitation, observing higher interaction infected prions. Our data is early replication, acting as neuroprotective factor neurotoxicity. findings suggest targeting have applications for developing novel strategies treatment diagnosis diseases.