17β‐Hydroxysteroid dehydrogenases and neurosteroid metabolism in the central nervous system

Abstract

17β‐Hydroxysteroid dehydrogenases are indispensable for neurosteroidogenesis. Neurosteroids are synthesized de novo in neurons and glia from cholesterol transported into mitochondria, or by conversion from proneurosteroids, e. g. dehydroepiandrosterone (DHEA) and pregnenolone, through the same metabolic pathway as de novo neurosteroidogenesis. Proneurosteroids are generated from endocrine glands—the adrenal cortex, ovary, and testis—and then transported into neurons and glia via the blood circulation. Non‐hormonal neurosteroids bind to cell surface receptors, e.g., GABAA or NMDA receptors and elicit antidepressant, anxiolytic, anticonvulsant and anesthetic effects by regulating neuroexcitabilty. Both non‐hormonal and hormonal neurosteroids play important roles in brain development including neuroprotection, neurogenesis and neural plasticity. They are also a critical element in cognitive and memory functions. Mitochondrial 17β‐HSD10, encoded by the HSD17B10 gene mapping to Xp11.2, is found in various brain regions, and is essential for the maintenance of neurosteroid homeostasis. Mutations identified in this gene result in two distinct brain diseases, namely HSD10 deficiency and MRXS10. Their clinical presentations and pathogenetic mechanisms are quite distinct, thus, it is not appropriate to combine them as a single “HSD10 disease”. Since elevated levels of 17β‐HSD10 is found in brains of Alzheimer's disease patients and AD mouse model, and this fascinating protein is responsible for the mitochondrial metabolism of neurosteroids such as 5α‐androstane‐3α,17β‐diol and 17β‐estradiol, analysis of the impact of 17β‐HSD10 and its inhibitor, “β‐amyloid peptide (Aβ),” on the metabolism of neuroactive steroids offers a new approach to AD pathogenesis.Support or Funding InformationNYS Office for People With Developmental DisabilitiesThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.