Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation.

Authors:
Avanita S Prabowo
Avanita S Prabowo
University of Amsterdam
Netherlands
Jasper J Anink
Jasper J Anink
University of Amsterdam
Netherlands
Martin Lammens
Martin Lammens
Antwerp University Hospital
Edegem | Belgium
Mark Nellist
Mark Nellist
Department of Clinical Genetics
Netherlands
Homa Adle-Biassette
Homa Adle-Biassette
Université Paris 7
France
Harvey B Sarnat
Harvey B Sarnat
University of Calgary Faculty of Medicine and Alberta Children's Hospital
Canada
Laura Flores-Sarnat
Laura Flores-Sarnat
Alberta Children's Hospital
Canada

Brain Pathol 2013 Jan 30;23(1):45-59. Epub 2012 Aug 30.

Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either the TSC1 or TSC2 genes and characterized by developmental brain abnormalities. We defined the spectrum of brain abnormalities in fetal TSC brain ranging from 23 to 38 gestational weeks. We hypothesized (i) prenatal activation of the target-of-rapamycin complex 1 (TORC1) signaling pathway; and (ii) activation of inflammatory pathways in fetal brain lesions. Immunocytochemical analysis of cortical tubers, as well as subependymal lesions in all cases confirmed the cell-associated activation of the TORC1 signaling pathway in both the cortical tubers and subependymal lesions (including a congenital subependymal giant cell astrocytoma) with expression of pS6, p4EBP1 and c-myc proteins, as well as of p70 S6 kinase 1. The lesions contained macrophages and T-lymphocytes; giant cells within the lesions expressed inflammatory response markers including major histocompatibility complex class I and II, Toll-like receptors (TLR) 2 and 4 and receptor for advanced glycation end products (RAGE). These observations indicate that brain malformations in TSC are likely a consequence of increased TORC1 activation during embryonic brain development. We also provide evidence supporting the possible immunogenicity of giant cells and the early activation of inflammatory pathways in TSC brain.

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http://dx.doi.org/10.1111/j.1750-3639.2012.00616.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518755PMC

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January 2013
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References

(Supplied by CrossRef)
Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation
Chan et al.
J Neuropathol Exp Neurol 2004

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