PT - JOURNAL ARTICLE AU - Marzo, Ludovica AU - Marijanovic, Zrinka AU - Browman, Duncan AU - Chamoun, Zeina AU - Caputo, Anna AU - Zurzolo, Chiara TI - 4-hydroxytamoxifen leads to PrP<sup>Sc</sup> clearance by conveying both PrP<sup>C</sup> and PrP<sup>Sc</sup> to lysosomes independently of autophagy AID - 10.1242/jcs.114801 DP - 2013 Mar 15 TA - Journal of Cell Science PG - 1345--1354 VI - 126 IP - 6 4099 - http://jcs.biologists.org/content/126/6/1345.short 4100 - http://jcs.biologists.org/content/126/6/1345.full SO - J. Cell Sci.2013 Mar 15; 126 AB - Prion diseases are fatal neurodegenerative disorders involving the abnormal folding of a native cellular protein, named PrPC, to a malconformed aggregation-prone state, enriched in beta sheet secondary structure, denoted PrPSc. Recently, autophagy has garnered considerable attention as a cellular process with the potential to counteract neurodegenerative diseases of protein aggregation such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. Stimulation of autophagy by chemical compounds has also been shown to reduce PrPSc in infected neuronal cells and prolong survival times in mouse models. Consistent with previous reports, we demonstrate that autophagic flux is increased in chronically infected cells. However, in contrast to recent findings we show that autophagy does not cause a reduction in scrapie burden. We report that in infected neuronal cells different compounds known to stimulate autophagy are ineffective in increasing autophagic flux and in reducing PrPSc. We further demonstrate that tamoxifen and its metabolite 4-hydroxytamoxifen lead to prion degradation in an autophagy-independent manner by diverting the trafficking of both PrP and cholesterol to lysosomes. Our data indicate that tamoxifen, a well-characterized, widely available pharmaceutical, may have applications in the therapy of prion diseases.