<p>Prion diseases are a group of fatal neurodegenerative diseases affecting almost all mammals including humans. The diseases are caused by formation of the misfolded isoform of the cellular prion protein (PrP<sup>C</sup>) to the disease causing PrP<sup>Sc</sup>. The focus on this work has been to characterize molecular changes in persistently scrapie-infected murine neuronal cells possibly contributing to prion-induced neurodegeneration. PrP<sup>C</sup> is localized to lipid rafts in the plasma membrane and this is also the place where it is suggested that the conformational change into PrP<sup>Sc</sup> occurs. This work shows an increased expression of active Src kinase in scrapie-infected cells resulting in an increased overall tyrosine phosphorylation of several proteins. Additionally, an increase in the specific tyrosine kinase activity of Fyn is shown. Interestingly, the membrane distribution of Fyn from non-raft to raft-domains followed that of PrP<sup>Sc</sup> in scrapie-infected cells as analyzed by immunoblotting of flotation-fractions after ultracentrifugation of Triton X-100 extracted cell lysates. This indicates a persistent Fyn activation, probably due to clustering of intracellular Fyn kinases due to PrP<sup>Sc</sup> accumulation in lipid rafts. In addition to an increased Src family kinase activity in scrapie-infected cells these cells also express an increased number of insulin receptor (IR)/insulin-like growth factor-1 receptor (IGF-1R) hybrid receptors, and these receptors display an altered protein glycosylation of the IR subunits. Additionally, ScN2a cells do not respond to LPS-stimulation with NO production, putatively due to the lack of CD14 mRNA. Together, these findings may have pathological implications leading to neuronal cell death in prion diseases via several mechanisms which are discussed in this thesis.</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:su-7115 |
| Date | January 2007 |
| Creators | Gyllberg, Hanna |
| Publisher | Stockholm University, Department of Biochemistry and Biophysics, Stockholm : Institutionen för biokemi och biofysik |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
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