Figure 9. Long-Term Estradiol Deprivation Leads to Brain-Specific Degradation of Unliganded Estrogen Receptor Alpha.
CHIP-mediated ubiquitination and proteasomal degradation of estrogen receptors (ER) in the hippocampal CA1 region occurs following long-term E2 deprivation (LTED) or natural aging. Long-term E2 deprivation or natural aging leads to an unliganded ER. The unliganded ER displays enhanced binding with the E3 ubiquitin ligase, CHIP, and the co-chaperone Bag1, leading to enhanced ubiquitination and proteasomal degradation of ER. The enhanced proteasomal degradation of ER leads to a decreased sensitivity of the hippocampal CA1 region to E2 and a correlated loss of E2 neuroprotection. Reprinted, with permission, from PNAS [202].