NDLI: Aberrant ERK 1/2 complex activation and localization in scrapie-infected GT1-1 cells

Content Provider	Springer Nature : BioMed Central
Author	Didonna, Alessandro Legname, Giuseppe
Abstract	Background Fatal neurodegenerative disorders such as Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases in humans, scrapie and bovine spongiform encephalopathy in animals, are characterized by the accumulation in the brain of a pathological form of the prion protein (PrP) denominated PrPSc. The latter derives from the host cellular form, PrPC, through a process whereby portions of its α-helical and coil structures are refolded into β-sheet structures. Results In this work, the widely known in vitro model of prion replication, hypothalamic GT1-1 cell line, was used to investigate cellular and molecular responses to prion infection. The MAP kinase cascade was dissected to assess the phosphorylation levels of src, MEK 1/2 and ERK 1/2 signaling molecules, both before and after prion infection. Our findings suggest that prion replication leads to a hyper-activation of this pathway. Biochemical analysis was complemented with immunofluorescence studies to map the localization of the ERK complex within the different cellular compartments. We showed how the ERK complex relocates in the cytosol upon prion infection. We correlated these findings with an impairment of cell growth in prion-infected GT1-1 cells as probed by MTT assay. Furthermore, given the persistent urgency in finding compounds able to cure prion infected cells, we tested the effects on the ERK cascade of two molecules known to block prion replication in vitro, quinacrine and Fab D18. We were able to show that while these two compounds possess similar effects in curing prion infection, they affect the MAP kinase cascade differently. Conclusions Taken together, our results help shed light on the molecular events involved in neurodegeneration and neuronal loss in prion infection and replication. In particular, the combination of chronic activation and aberrant localization of the ERK complex may lead to a lack of essential neuroprotective and survival factors. Interestingly, these data seem to define some common traits with other neurodegenerative disorders such as, for example, Alzheimer's disease.
Related Links	https://molecularneurodegeneration.biomedcentral.com/counter/pdf/10.1186/1750-1326-5-29.pdf
Ending Page	12
Page Count	12
Starting Page	1
File Format	HTM / HTML
ISSN	17501326
DOI	10.1186/1750-1326-5-29
Journal	Molecular Neurodegeneration
Issue Number	1
Volume Number	5
Language	English
Publisher	BioMed Central
Publisher Date	2010-08-09
Access Restriction	Open
Subject Keyword	Neurosciences Neurology Molecular Medicine Prion Disease Bovine Spongiform Encephalopathy Scrapie Uninfected Cell Quinacrine
Content Type	Text
Resource Type	Article
Subject	Neurology (clinical) Molecular Biology Cellular and Molecular Neuroscience
Journal Impact Factor	15.1/2023
5-Year Journal Impact Factor	16.8/2023

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