In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 35 ( 2011-08-30)
Abstract:
To address these issues, we examined the ubiquitination and degradation of ERα and ERβ in the hippocampal CA1 region of female rats following long-term deprivation or natural aging. In addition, we determined the role of CHIP in ubiquitination and degradation of ERα/ERβ and examined whether changes in ERα/ERβ were correlated with changes in the sensitivity of the hippocampal CA1 to neuroprotection during natural aging. Here, we show that ERα in the rat hippocampal CA1 region but not the uterus undergoes enhanced interaction with the enzyme CHIP and Bag-1 that leads to its ubiquitination/proteasomal degradation following long-term deprivation. Estrogen treatment initiated before but not after long-term deprivation prevented the enhanced ERα-CHIP/Bag-1 interaction and ERα ubiquitination/degradation, and it was fully neuroprotective against GCI. Administration of a proteasomal inhibitor or antisense oligonucleotides to CHIP reversed the long-term deprivation-induced down-regulation of ERα. Important questions are whether these observations in the long-term deprivation model are relevant to natural aging and whether there is an age-related critical period for neuroprotection in the hippocampus. Here, we show that these observations do extend to natural aging, because aged (24-mo-old) rats showed enhanced CHIP/Bag-1 interaction, ubiquitination, and degradation of both hippocampal ERα and ERβ as well as, importantly, a correlated loss of neuroprotection against GCI. In contrast, estrogen administration to middle-aged (10-mo-old) rats was still capable of exerting neuroprotection. As a whole, the study provides support for a critical period for neuroprotection of the hippocampus. Previous work by our laboratory and others revealed that long-term estrogen deprivation leads to a loss of neuroprotection in animal models of focal and global cerebral ischemia (GCI). Furthermore, we recently showed that the loss of neuroprotection of the hippocampal CA1 region was correlated with a significant decrease in the α- but not β-subunit of the ER ( 2 ). This decrease in ERα and estrogen sensitivity was tissue-specific, because ERα did not decrease in the uterus following long-term deprivation and the uterus, unlike the hippocampal CA1 region, remained sensitive to the action of estrogen. The mechanisms underlying the decrease of ERα in the hippocampal CA1 region following long-term deprivation are unknown. Previous work in breast cancer cells demonstrated that the enzyme CHIP binds and promotes degradation of the unliganded ERα via the ubiquitin-proteasome degradation pathway ( 3 , 4 ). Because long-term deprivation results in very low serum estrogen levels, we hypothesized that the reduced levels of ERα in the hippocampal CA1 following long-term deprivation may be attributable to CHIP-mediated proteasomal degradation of ERα. Furthermore, because long-term deprivation is only a model of aging, it was important to determine whether ERα levels and estrogen sensitivity of the hippocampal CA1 region are similarly attenuated with natural aging. The beneficial effects of estrogen, or 17β-estradiol, replacement on cardiovascular disease and neurodegenerative diseases, such as stroke and Alzheimer's disease, are well known ( 1 ). However, the National Institutes of Health's Women's Health Initiative (WHI), a 15-y study of more than 12,000 postmenopausal women, surprisingly failed to observe a protective effect of hormone replacement therapy on the cardiovascular system and reported a small but significant increase in risk for stroke and dementia. The average age of subjects in the WHI study was 63 y, far past the onset of menopause. It has been suggested that there may be a “critical period” for the beneficial protective effect of estrogen on the brain and that the hormone may need to be administered around menopause or earlier to observe a beneficial effect on the cardiovascular and neural systems. Here, we provide evidence supporting the existence of a critical period for the neuroprotective effect of estrogen in the hippocampal CA1 region, a region critical for cognition, learning, and memory. We further demonstrate a potential mechanism for the critical period by demonstrating that an enzyme called carboxyl terminus of Hsc70-interacting protein (CHIP) binds and promotes degradation of the α-subunit of the estrogen receptor (ER) in the female rat hippocampal CA1 region following long-term estrogen deprivation and natural aging. We show that in periods of low circulating estrogen levels, the unliganded ER displays increased binding to CHIP, leading to its ubiquitination, a posttranslational modification ( Fig. P1 ). We also show enhanced interaction of ER and CHIP with the protein, Bcl-2–associated athanogene 1 (Bag-1), which has been implicated in the delivery of ubiquitinated proteins to the proteasome, a cellular organelle where protein degradation occurs. The proteasomal degradation of ER is proposed to underlie decreased sensitivity of the hippocampus to the hormone and a corresponding loss of neuroprotection that was observed after long-term deprivation and in aged rats ( Fig. P1 ).
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1104391108
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2011
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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