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It has been suggested that defects in neuronal differentiation and\/or migration underlie the appearance of tubers. However, the precise molecular alterations remain largely unknown. Here, by combining cytological and immunohistochemical analyses of tubers from nine <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> patients (four of them diagnosed with <jats:italic><jats:styled-content style=\"fixed-case\">TSC2<\/jats:styled-content><\/jats:italic> germline mutations), we show that alteration of microtubule biology through <jats:styled-content style=\"fixed-case\">ROCK2<\/jats:styled-content> signalling contributes to <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> neuropathology. All tubers showed a larger number of binucleated neurons than expected relative to control cortex. An excess of normal and altered cytokinetic figures was also commonly observed. Analysis of centrosomal markers suggested increased microtubule nucleation capacity, which was supported by the analysis of an expression dataset from cortical tubers and control cortex, and subsequently linked to under\u2010expression of Rho\u2010associated coiled\u2010coil containing kinase 2 (<jats:styled-content style=\"fixed-case\">ROCK2<\/jats:styled-content>). Thus, augmented microtubule nucleation capacity was observed in mouse embryonic fibroblasts and human fibroblasts deficient in the <jats:italic>Tsc2\/<jats:styled-content style=\"fixed-case\">TSC2<\/jats:styled-content><\/jats:italic> gene product, tuberin. Consistent with <jats:styled-content style=\"fixed-case\">ROCK2<\/jats:styled-content> under\u2010expression, microtubule acetylation was found to be increased with tuberin deficiency; this alteration was abrogated by rapamycin treatment and mimicked by <jats:styled-content style=\"fixed-case\">HDAC6<\/jats:styled-content> inhibition. Together, the results of this study support the hypothesis that loss of <jats:italic><jats:styled-content style=\"fixed-case\">TSC2<\/jats:styled-content><\/jats:italic> expression can alter microtubule organization and dynamics, which, in turn, deregulate cell division and potentially impair neuronal differentiation. Copyright \u00a9 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd<\/jats:p>","DOI":"10.1002\/path.4343","type":"journal-article","created":{"date-parts":[[2014,3,6]],"date-time":"2014-03-06T09:21:07Z","timestamp":1394097667000},"page":"247-257","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Tubers from patients with tuberous sclerosis complex are characterized by changes in microtubule biology through <scp>ROCK2<\/scp> signalling"],"prefix":"10.1002","volume":"233","author":[{"given":"Isidre","family":"Ferrer","sequence":"first","affiliation":[{"name":"Institute of Neuropathology University Hospital Bellvitge, University of Barcelona, Bellvitge Institute for Biomedical Research (IDIBELL), CIBERNED, L'Hospitalet del Llobregat  Barcelona Catalonia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pooja","family":"Mohan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of British 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