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Tubers from patients with tuberous sclerosis complex are characterized by changes in microtubule biology through ROCK2 signalling
Author(s) -
Ferrer Isidre,
Mohan Pooja,
Chen Helen,
Castellsague Joan,
GómezBaldó Laia,
Carmona Marga,
García Nadia,
Aguilar Helena,
Jiang Jihong,
Skowron Margaretha,
Nellist Mark,
Ampuero Israel,
Russi Antonio,
Lázaro Conxi,
Maxwell Christopher A,
Pujana Miguel Angel
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4343
Subject(s) - tsc2 , tuberous sclerosis , biology , microtubule , rock2 , microbiology and biotechnology , tsc1 , rhoa , cortex (anatomy) , kinase , rho associated protein kinase , signal transduction , pi3k/akt/mtor pathway , pathology , neuroscience , medicine
Most patients with tuberous sclerosis complex ( TSC ) develop cortical tubers that cause severe neurological disabilities. 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 TSC patients (four of them diagnosed with TSC2 germline mutations), we show that alteration of microtubule biology through ROCK2 signalling contributes to TSC 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‐expression of Rho‐associated coiled‐coil containing kinase 2 ( ROCK2 ). Thus, augmented microtubule nucleation capacity was observed in mouse embryonic fibroblasts and human fibroblasts deficient in the Tsc2/ TSC2 gene product, tuberin. Consistent with ROCK2 under‐expression, microtubule acetylation was found to be increased with tuberin deficiency; this alteration was abrogated by rapamycin treatment and mimicked by HDAC6 inhibition. Together, the results of this study support the hypothesis that loss of TSC2 expression can alter microtubule organization and dynamics, which, in turn, deregulate cell division and potentially impair neuronal differentiation. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

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