Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation.
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.
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam.
Avanita S
AS
Prabowo
Jasper J
JJ
Anink
Martin
M
Lammens
Mark
M
Nellist
Ans M W
AM
van den Ouweland
Homa
H
Adle-Biassette
Harvey B
HB
Sarnat
Laura
L
Flores-Sarnat
Peter B
PB
Crino
Eleonora
E
Aronica
D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004252:DNA Mutational Analysis; D004660:Encephalitis / Q000209:etiology*; D005260:Female; D005333:Fetus; D015972:Gene Expression Regulation, Neoplastic; D005865:Gestational Age; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011247:Pregnancy; D011296:Prenatal Diagnosis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000150:complications* / Q000473:pathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
D015703:Antigens, CD; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D051193:Toll-Like Receptors; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases