A Cell-Biased Effect of Estrogen in Prion Infection

作者：Molloy Brendan; McMahon Hilary E M^*

来源：Journal of Virology, 2014, 88(2): 1342-1353.

DOI：10.1128/JVI.02936-13

Prion disorders are associated with the accumulation of a misfolded form (PrPSc) of the normal prion protein, PrPC. 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 alpha and Er beta. By using specific receptor agonists, Er alpha was found to be the main receptor active in slowing prion infection, whereas in chronically infected cells, although Er alpha allowed partial maintenance of PrPSc levels, Er beta was the main receptor involved in maintaining PrPSc 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), PrPSc could be cleared from prion-infected cell culture. Tam and OHT had half-maximal inhibitory concentrations for clearance of PrPSc of 0.47 mu 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 PrPSc levels.

• 出版日期2014-1