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The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5α-Reductase?
Tourette's syndrome (TS) is a neurodevelopmental disorder characterised by recurring motor and phonic tics. The pathogenesis of TS is considered to reflect dysregulations in the signalling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico‐st...
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| Published in: | Journal of neuroendocrinology 2013-11, Vol.25 (11), p.1196-1208 |
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| creator | Bortolato, M. Frau, R. Godar, S. C. Mosher, L. J. Paba, S. Marrosu, F. Devoto, P. |
| description | Tourette's syndrome (TS) is a neurodevelopmental disorder characterised by recurring motor and phonic tics. The pathogenesis of TS is considered to reflect dysregulations in the signalling 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 approximately 4 : 1. Converging lines of evidence point to neuroactive steroids as being likely molecular candidates to account for G × E × S 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 catalysing 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 hypothesise 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 signalling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioural abnormalities in TS. |
| doi_str_mv | 10.1111/jne.12066 |
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C. ; Mosher, L. J. ; Paba, S. ; Marrosu, F. ; Devoto, P.</creator><creatorcontrib>Bortolato, M. ; Frau, R. ; Godar, S. C. ; Mosher, L. J. ; Paba, S. ; Marrosu, F. ; Devoto, P.</creatorcontrib><description>Tourette's syndrome (TS) is a neurodevelopmental disorder characterised by recurring motor and phonic tics. The pathogenesis of TS is considered to reflect dysregulations in the signalling 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 approximately 4 : 1. Converging lines of evidence point to neuroactive steroids as being likely molecular candidates to account for G × E × S 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 catalysing 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 hypothesise 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 signalling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioural abnormalities in TS.</description><identifier>ISSN: 0953-8194</identifier><identifier>EISSN: 1365-2826</identifier><identifier>DOI: 10.1111/jne.12066</identifier><identifier>PMID: 23795653</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>androgens ; Androgens - biosynthesis ; Androgens - physiology ; Cholestenone 5 alpha-Reductase - antagonists & inhibitors ; Cholestenone 5 alpha-Reductase - physiology ; dopamine ; Female ; Gene-Environment Interaction ; Humans ; Male ; neuroactive steroids ; Neurotransmitter Agents - biosynthesis ; Neurotransmitter Agents - physiology ; Sex Factors ; steroids ; Tourette Syndrome - etiology ; Tourette Syndrome - genetics ; Tourette Syndrome - metabolism</subject><ispartof>Journal of neuroendocrinology, 2013-11, Vol.25 (11), p.1196-1208</ispartof><rights>2013 British Society for Neuroendocrinology</rights><rights>2013 British Society for Neuroendocrinology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4316-8a1b95a669579f6f79906d10f1974f13bb9cc3410b347d7cfb2cf018ab15d3b23</citedby><cites>FETCH-LOGICAL-c4316-8a1b95a669579f6f79906d10f1974f13bb9cc3410b347d7cfb2cf018ab15d3b23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjne.12066$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjne.12066$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23795653$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bortolato, M.</creatorcontrib><creatorcontrib>Frau, R.</creatorcontrib><creatorcontrib>Godar, S. C.</creatorcontrib><creatorcontrib>Mosher, L. J.</creatorcontrib><creatorcontrib>Paba, S.</creatorcontrib><creatorcontrib>Marrosu, F.</creatorcontrib><creatorcontrib>Devoto, P.</creatorcontrib><title>The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5α-Reductase?</title><title>Journal of neuroendocrinology</title><addtitle>J Neuroendocrinol</addtitle><description>Tourette's syndrome (TS) is a neurodevelopmental disorder characterised by recurring motor and phonic tics. The pathogenesis of TS is considered to reflect dysregulations in the signalling 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 approximately 4 : 1. Converging lines of evidence point to neuroactive steroids as being likely molecular candidates to account for G × E × S 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 catalysing 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 hypothesise 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 signalling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioural abnormalities in TS.</description><subject>androgens</subject><subject>Androgens - biosynthesis</subject><subject>Androgens - physiology</subject><subject>Cholestenone 5 alpha-Reductase - antagonists & inhibitors</subject><subject>Cholestenone 5 alpha-Reductase - physiology</subject><subject>dopamine</subject><subject>Female</subject><subject>Gene-Environment Interaction</subject><subject>Humans</subject><subject>Male</subject><subject>neuroactive steroids</subject><subject>Neurotransmitter Agents - biosynthesis</subject><subject>Neurotransmitter Agents - physiology</subject><subject>Sex Factors</subject><subject>steroids</subject><subject>Tourette Syndrome - etiology</subject><subject>Tourette Syndrome - genetics</subject><subject>Tourette Syndrome - metabolism</subject><issn>0953-8194</issn><issn>1365-2826</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp1kM1u1DAURi0EotPCghdA3gGLtHb8F7OpSlVKUTWgdhASG8txrqlLEg-2U5jH4kV4JgLTdsfd3M35zuIg9IySfTrfwfUI-7QmUj5AC8qkqOqmlg_RgmjBqoZqvoN2c74mhCrByGO0UzOlhRRsgfzqCvDZsO6DsyXEEUePlzClaF0JN4AvC6QYuozDiFdxSlAKvMj4cjN2KQ6AP9pyFb_CCDnk1_gIX8QesI8Ji9-_qgvoJldshsMn6JG3fYant38PfXp7sjp-V51_OD07PjqvHGdUVo2lrRZWSi2U9tIrrYnsKPFUK-4pa1vtHOOUtIyrTjnf1s4T2tiWio61NdtDL7fedYrfJ8jFDCE76Hs7QpyyoVxyQXnTkBl9tUVdijkn8GadwmDTxlBi_mY1c1bzL-vMPr_VTu0A3T1513EGDrbAj9DD5v8m8355cqestouQC_y8X9j0zUjFlDCfl6eGNUy_-SK40ewPdQKQWg</recordid><startdate>201311</startdate><enddate>201311</enddate><creator>Bortolato, M.</creator><creator>Frau, R.</creator><creator>Godar, S. 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J. ; Paba, S. ; Marrosu, F. ; Devoto, P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4316-8a1b95a669579f6f79906d10f1974f13bb9cc3410b347d7cfb2cf018ab15d3b23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>androgens</topic><topic>Androgens - biosynthesis</topic><topic>Androgens - physiology</topic><topic>Cholestenone 5 alpha-Reductase - antagonists & inhibitors</topic><topic>Cholestenone 5 alpha-Reductase - physiology</topic><topic>dopamine</topic><topic>Female</topic><topic>Gene-Environment Interaction</topic><topic>Humans</topic><topic>Male</topic><topic>neuroactive steroids</topic><topic>Neurotransmitter Agents - biosynthesis</topic><topic>Neurotransmitter Agents - physiology</topic><topic>Sex Factors</topic><topic>steroids</topic><topic>Tourette Syndrome - etiology</topic><topic>Tourette Syndrome - genetics</topic><topic>Tourette Syndrome - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bortolato, M.</creatorcontrib><creatorcontrib>Frau, R.</creatorcontrib><creatorcontrib>Godar, S. C.</creatorcontrib><creatorcontrib>Mosher, L. J.</creatorcontrib><creatorcontrib>Paba, S.</creatorcontrib><creatorcontrib>Marrosu, F.</creatorcontrib><creatorcontrib>Devoto, P.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><jtitle>Journal of neuroendocrinology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bortolato, M.</au><au>Frau, R.</au><au>Godar, S. C.</au><au>Mosher, L. J.</au><au>Paba, S.</au><au>Marrosu, F.</au><au>Devoto, P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5α-Reductase?</atitle><jtitle>Journal of neuroendocrinology</jtitle><addtitle>J Neuroendocrinol</addtitle><date>2013-11</date><risdate>2013</risdate><volume>25</volume><issue>11</issue><spage>1196</spage><epage>1208</epage><pages>1196-1208</pages><issn>0953-8194</issn><eissn>1365-2826</eissn><notes>ArticleID:JNE12066</notes><notes>National Institute of Health - No. R21 HD070611</notes><notes>Translational Science Award grant - No. UL1 TR000001; No. UL1RR033179</notes><notes>Sardinia Regional Research Grant</notes><notes>ark:/67375/WNG-3839BZ54-9</notes><notes>istex:0E12AFF73DD307F0D00CCBC6AC2EF5A421FE89E9</notes><notes>National Institute of General Medical Sciences - No. P20 GM103638</notes><notes>Tourette Syndrome Association</notes><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><abstract>Tourette's syndrome (TS) is a neurodevelopmental disorder characterised by recurring motor and phonic tics. The pathogenesis of TS is considered to reflect dysregulations in the signalling 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 approximately 4 : 1. Converging lines of evidence point to neuroactive steroids as being likely molecular candidates to account for G × E × S 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 catalysing 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 hypothesise 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 signalling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioural abnormalities in TS.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>23795653</pmid><doi>10.1111/jne.12066</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | androgens Androgens - biosynthesis Androgens - physiology Cholestenone 5 alpha-Reductase - antagonists & inhibitors Cholestenone 5 alpha-Reductase - physiology dopamine Female Gene-Environment Interaction Humans Male neuroactive steroids Neurotransmitter Agents - biosynthesis Neurotransmitter Agents - physiology Sex Factors steroids Tourette Syndrome - etiology Tourette Syndrome - genetics Tourette Syndrome - metabolism |
| title | The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5α-Reductase? |
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