Estrogens (estrone, estriol, and estradiol) are a class of steroidal hormones produced by developing ovarian follicles. These hormones induce various cyclic events in the uterine endothelium and vaginal epithelium and make the female body competent for conception and ultimately for motherly care. While estrogen is primarily produced by ovaries from cholesterol, the non-reproductive tissues including the brain, liver, and heart also produce a considerable amount of it. Apart from its important role in controlling sexual behavior and reproductive function, estrogen also functions in the regulation of various physiological functions including reproduction, skin physiology, cardiovascular health, skeletal homeostasis, bone integrity, electrolyte balance, cognition, and behavior. These biological functions are regulated by diffusion through the plasma membrane in vitro signaling through specific binding to nuclear receptors such as estrogen receptors (ERα and ERβ) or binding to cell membrane receptors such as GPR30 and ER-X. The signaling mechanism can be genomic (change in gene expression) or non-genomic (activation of various signaling cascades). Disruption in estrogen functioning has a pivotal role in the pathogenesis of many diseases such as osteoporosis, insulin resistance, neurodegenerative disease, obesity, and endometriosis. Also, dysregulation in the levels of estrogen has been linked to the development of many cancers such as breast cancer, etc. This chapter aims to summarize the complete insight of estrogen by providing a clear understanding of its synthesis, receptor binding, signaling, regulation of physiological functions, and role in various diseases.
Cellular chaperones are essential players to this protein quality control network that functions to prevent protein misfolding, refold misfolded proteins, or degrade them, thereby maintaining neuronal proteostasis. Moreover, overexpression of cellular chaperones is considered to inhibit protein aggregation and apoptosis in various experimental models of neurodegeneration. Alterations or downregulation of chaperone machinery by age-related decline, molecular crowding, or genetic mutations are regarded as key pathological hallmarks of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Prion diseases. Therefore, chaperones may serve as potential therapeutic targets in these diseases. This chapter presents a generalized view of misfolding and aggregation of proteins in neurodegeneration and then critically analyses some of the known cellular chaperones and their role in several neurodegenerative disorders.
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Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.
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