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The implication of neuroactive steroids in Tourette syndrome pathogenesis: a role for 5α-reductase?
Bortolato, Marco Frau, Roberto Godar, Sean C. Mosher, Laura J. Paba, Silvia Marrosu, Francesco Devoto, Paola
Bortolato, Marco
Frau, Roberto
Godar, Sean C.
Mosher, Laura J.
Paba, Silvia
Marrosu, Francesco
Devoto, Paola
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Abstract
Tourette syndrome (TS) is a neurodevelopmental disorder characterized by recurring motor and phonic tics. The pathogenesis of TS is thought to reflect dysregulations in the signaling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene × environment × sex (G×E×S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of ~4:1. Converging lines of evidence point to neuroactive steroids as likely molecular candidates to account for GxExS interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5α-reductase (5αR), the enzyme catalyzing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesize that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the “backdoor” pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signaling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioral abnormalities in TS.
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This is the peer reviewed version of the following article: Bortolato, M., Frau, R., Godar, S. C., Mosher, L. J., Paba, S., Marrosu, F. and Devoto, P. (2013), The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5α-Reductase?. J Neuroendocrinol, 25: 1196–1208. doi:10.1111/jne.12066, which has been published in final form at http://doi.org/10.1111/jne.12066. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
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2013-11
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Wiley
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Bortolato, M., Frau, R., Godar, S. C., Mosher, L. J., Paba, S., Marrosu, F. and Devoto, P. (2013), The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5α-Reductase?. J Neuroendocrinol, 25: 1196–1208. doi:10.1111/jne.12066