Estrogen and androgen regulation of the small heat shock protein ±A-crystallin: New perspectives on sex steroid implication in age-related disorders associated with proteotoxic stress.

Sex steroids, here especially referring to estrogens and androgens, have an important impact on the anatomy, physiology and pathophysiology of the eye and brain. Gender dissimilarities are reported in the structural and functional organization of ocular and brain tissues and there is compelling evidence that fluctuations in the levels of sex steroids during life affect neural functions. Studies especially highlight their critical role in the pathogenesis of age-related ocular diseases just as neurodegenerative diseases, which share the common pathological mechanism of protein aggregation. For instance, estrogen depletion in postmenopausal women is associated with higher risk of developing age-related macular degeneration (AMD) as well as Alzheimer's disease, and risks seem to be relieved among postmenopausal hormone users (1-2). An estrogen receptor repressor induces cataract formation in transgenic mice and androgen effects are associated with dry eye syndromes. Human and mammalian ocular and brain tissues possess estrogen receptor subtypes androgen receptors and enzymes of synthesis and metabolism of their ligands. Our own investigations set the adult retina as an androgenic and estrogenic tissue where synthesis and function of testosterone and its transformed product estradiol may rely on the control of aromatase and presence of ER?, ER? and ARs (3), and they are both involved in survival mechanisms during in vitro retinal ischemia (4). However, the functional pathways of sex steroids are only partly understood and the broad range of their effects makes it plausible that many target molecules are still unknown. Using the intravitreal injection technique, which is a mainstay of ophthalmic practice, 2-DE gels and MALDI-TOF-MS analyses we explored the effects of treatments with the bioactive 17?-estradiol or androgen dihydrotestosterone (DHT) on the retinal proteome. We identified three sex steroid-regulated proteins: the galectin-related-inter-fiber (GRIFIN) which is a galectin family member protein of unknown function, the fatty acid-binding epidermal- 5 (FABP5) protein responsible for the fatty acid uptake and transport, and the small heat shock ?A-crystallin (CRYAA) protein involved in preventing aggregation of denatured or unfolded proteins. This study first demonstrates the regulation of these proteins after intravitreal injection of sex steroids. It is noteworthy that CRYAA, estrogens and androgens have antioxidant and antiapoptotic properties and reduce amyloid ?- peptide accumulation and toxicity (5); moreover, age-related ocular and neurodegenerative protein misfolding diseases are associated with crystallins changes and sex steroid depletion. Although some clinical studies disclose benefits among hormone therapy users, the therapeutic value of estrogens and androgens is far to be definitive and studies are needed. Our findings on sex steroid-mediated regulation of ?A-crystallin, GRIFIN and FABP5 give evidence for novel mechanism(s) of sex steroids and a potential link to age-related disorders associated with proteotoxic stress.