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- W182440317 abstract "The physiological function of the cellular prion protein (PrPC) and its contribution to prion diseases remains enigmatic as evidence suggests both pro- and anti-apoptotic functions. The data presented here suggest PrPC is expressed in two topological isoforms with unique functional manifestations and with the participation of both in the pathogenesis of prion disease. Expression of two topological isoforms were identified in wild type mice, a fully secreted isoform, designated SecPrP and a small fraction as a single spanning transmembrane isoform designated CtmPrP. By introducing mutations that favor expression in either SecPrP or CtmPrP the functional role of each form was dissected. Transgenic mice that favor CtmPrP expression develop spontaneous neurodegeneration with evidence of apoptotic cell death. Further investigation in cultured mammalian cells identified a Bax and caspase-3 dependant pathway by which CtmPrP triggers apoptosis in a dose dependant manner. In contrast, SecPrP reveals a protective role against apoptosis as seen in the hippocampus of transgenic mice challenged with kainic acid which otherwise leads to dramatic cell death by increased oxidative stress. The observation was made that CtmPrP favoring mice are most vulnerable to kainic acid mediated neurodegeneration where as SecPrP favoring mice are the least vulnerable to the same treatment. The protective role of SecPrP against oxidative stress was confirmed in cultured mammalian cells and primary cultured neurons. Finally, the contribution of each isoform was assessed in mice inoculated with prions (PrPSc). Mice favoring expression in the CtmPrP form developed symptoms at ~50 days and showed focal accumulation of PrPSc and neurodegeneration proximal to the inoculation site with indications of both apoptotic and oxidative stress related degeneration. Mice favoring expression in the SecPrP form develop symptoms at ~320 days with accumulation of PrPSc throughout the brain yet only show signs of oxidative stress related damage. In conclusion, evidence is provided that wild type PrPC has the intrinsic capacity to be expressed as either SecPrP or CtmPrP and that each isoform can partake in independent pathways. SecPrP participates in a neuroprotective pathway against oxidative stress whereas CtmPrP activates a caspase-3 dependant apoptotic pathway. Further evidence suggests that both isoforms participate in the etiology of infectious prion disease: upregulation of CtmPrP which leads to apoptosis and conversion of SecPrP to PrPSc and its down regulation lead to a higher susceptibility to oxidative stress, thus being able to reconcile how both gain and loss of PrPC functions may occur." @default.
- W182440317 created "2016-06-24" @default.
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- W182440317 date "2008-01-01" @default.
- W182440317 modified "2023-09-26" @default.
- W182440317 title "Bifunctional roles for two topological isoforms of the cellular prion protein" @default.
- W182440317 hasPublicationYear "2008" @default.
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