A Cell-Biased Effect of Estrogen in Prion Infection

Abstract

Prion disorders are associated with the accumulation of a misfolded form (PrP Sc ) of the normal prion protein, PrP C . Here, we show that estrogen acts as a regulator of the processes of both prion infection and prion maintenance. Estrogen was found to be cell biased in its effect; it protected cells against prion infection in a prevention mode and enabled prion maintenance in a treatment mode. These processes were regulated by the estrogen receptor subtypes Er␣ and Er␤. By using specific receptor agonists, Er␣ was found to be the main receptor active in slowing prion infection, whereas in chronically infected cells, although Er␣ allowed partial maintenance of PrP Sc levels, Er␤ was the main receptor involved in maintaining PrP Sc in a treatment paradigm. A cell-biased effect of estrogen has been reported for other neurodegenerative disorders, including Alzheimer's disease. Estrogen's effect is dependent on the cell's health status, which impacts the use of estrogen. This work also identified that by targeting the estrogen receptors with the selective estrogen receptor modulators tamoxifen (Tam) and 4-hydroxy-tamoxifen (OHT), PrP Sc could be cleared from prion-infected cell culture. Tam and OHT had half-maximal inhibitory concentrations for clearance of PrP Sc of 0.47 M and 0.14 nM, respectively. This work identifies further factors involved in the prion disease process, and through antagonism of the estrogen system, we demonstrate that the estrogen system is a target for controlling PrP Sc levels.

A nationwide trend analysis in the incidence and mortality of Creutzfeldt–Jakob disease in Japan between 2005 and 2014

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Estradiol attenuates LPS-induced acute lung injury via induction of aquaporins AQP1 and AQP5

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