Tubers from patients with tuberous sclerosis complex are characterized by changes in microtubule biology through ROCK2 signalling
Autor: | Antonio Russi, Mark Nellist, Conxi Lázaro, Joan Castellsague, Jihong Jiang, Christopher A. Maxwell, Nadia García, Helen Chen, Miguel Angel Pujana, Isidre Ferrer, Israel Ampuero, Laia Gómez-Baldó, Helena Aguilar, Pooja Mohan, Marga Carmona, Margaretha A. Skowron |
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Rok vydání: | 2014 |
Předmět: |
Cortical tubers
congenital hereditary and neonatal diseases and abnormalities 0303 health sciences Cell division Kinase food and beverages Biology medicine.disease Pathology and Forensic Medicine Cell biology 03 medical and health sciences Tuberous sclerosis 0302 clinical medicine Microtubule medicine ROCK2 TSC2 030217 neurology & neurosurgery 030304 developmental biology Microtubule nucleation |
Zdroj: | The Journal of Pathology. 233:247-257 |
ISSN: | 0022-3417 |
Popis: | 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 |
Databáze: | OpenAIRE |
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