Open AccessFetal Brain Lesions in Tuberous Sclerosis Complex: TORC1 Activation and Inflammation
Author(s) -
Prabowo Avanita S.,
Anink Jasper J.,
Lammens Martin,
Nellist Mark,
den Ouweland Ans M. W.,
AdleBiassette Homa,
Sarnat Harvey B.,
FloresSarnat Laura,
Crino Peter B.,
Aronica Eleonora
Publication year - 2013
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.2012.00616.x
Subject(s) - subependymal zone , tuberous sclerosis , tsc1 , biology , tsc2 , inflammation , cancer research , pathology , signal transduction , medicine , immunology , neuroscience , pi3k/akt/mtor pathway , microbiology and biotechnology
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.