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In addition to being the precursor of steroids, PREG acts directly on various targets including microtubules (MTs), the functioning of which is fundamental for the development and homeostasis of nervous system. The coordination of MT dynamics is supported by a plethora of MT\u2010associated proteins (MAPs) and by a specific MT code that is defined by the post\u2010translational modifications of tubulin. Defects associated with MAPs or tubulin post\u2010translational modifications are linked to different neurological pathologies including mood and neurodevelopmental disorders. In this review, we describe the beneficial effect of PME in major depressive disorders (MDDs) and in CDKL5 deficiency disorder (CDD), two pathologies that are joint by defective MT dynamics. Growing evidence indeed suggests that PME, as well as PREG, is able to positively affect the MT\u2010binding of MAP2 and the plus\u2010end tracking protein CLIP170 that are both found to be deregulated in the above mentioned pathologies. Furthermore, PME influences the state of MT acetylation, the deregulation of which is often associated with neurological abnormalities including MDDs. By contrast to PREG, PME is not metabolised into other downstream molecules with specific biological properties, an aspect that makes this compound more suitable for therapeutic strategies. Thus, through the analysis of MDDs and CDD, this work focuses attention on the possible use of PME for neuronal pathologies associated with MT defects.<\/jats:p>","DOI":"10.1111\/jne.13033","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T04:40:11Z","timestamp":1629348011000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Therapeutic potential of pregnenolone and pregnenolone methyl ether on depressive and CDKL5 deficiency disorders: Focus on microtubule targeting"],"prefix":"10.1111","volume":"34","author":[{"given":"Isabella","family":"Barbiero","sequence":"first","affiliation":[{"name":"Department of Biotechnology and Life Sciences, (DBSV) Centre of NeuroScience University of Insubria  Busto Arsizio Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Ulysses Neuroscience Ltd. 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