Endolysosome Localization of ERa Is Involved in the Protective Effect of 17a-Estradiol against HIV-1 gp120-Induced Neuronal Injury

Abstract

Neurotoxic HIV-1 viral proteins contribute to the development of HIV-associated neurocognitive disorder (HAND), the prevalence of which remains high (30–50%) with no effective treatment available. Estrogen is a known neuroprotective agent; however, the diverse mechanisms of estrogen action on the different types of estrogen receptors is not completely understood. In this study, we determined the extent to which and mechanisms by which 17a-estradiol (17aE2), a natural less-feminizing estrogen, offers neuroprotection against HIV-1 gp120-induced neuronal injury. Endolysosomes are important for neuronal function, and endolysosomal dysfunction contributes to HAND and other neurodegenerative disorders. In hippocampal neurons, estrogen receptor a (ERa) is localized to endolysosomes and 17aE2 acidifies endolysosomes. ERa knockdown or overexpressing an ERa mutant that is deficient in endolysosome localization prevents 17aE2-induced endolysosome acidification. Furthermore, 17aE2-induced increases in dendritic spine density depend on endolysosome localization of ERa. Pretreatment with 17aE2 protected against HIV-1 gp120-induced endolysosome deacidification and reductions in dendritic spines; such protective effects depended on endolysosome localization of ERa. In male HIV-1 transgenic rats, we show that 17aE2 treatment prevents the development of enlarged endolysosomes and reduction in dendritic spines. Our findings demonstrate a novel endolysosome-dependent pathway that governs the ERa-mediated neuroprotective actions of 17aE2, findings that might lead to the development of novel therapeutic strategies against HAND.