@article{4638202925884855bd81f010c18a8b48,
title = "Increased expression of complement components in tuberous sclerosis complex and focal cortical dysplasia type 2B brain lesions",
abstract = "OBJECTIVE: Increasing evidence supports the contribution of inflammatory mechanisms to the neurological manifestations of epileptogenic developmental pathologies linked to mammalian target of rapamycin (mTOR) pathway dysregulation (mTORopathies), such as tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD). In this study, we aimed to investigate the expression pattern and cellular distribution of the complement factors C1q and C3 in resected cortical tissue of clinically well-characterized patients with TSC and FCD2B.METHODS: We applied immunohistochemistry in TSC (n = 29) and FCD2B (n = 32) samples and compared them to autopsy and biopsy controls (n = 27). Furthermore, protein expression was observed via Western blot, and for descriptive colocalization studies immunofluorescence double labeling was performed.RESULTS: Protein expression for C3 was significantly upregulated in TSC and FCD2B white and gray matter lesions compared to controls. Staining of the synaptic vesicle protein synaptophysin showed a remarkable increase in the white matter of both TSC and FCD2B. Furthermore, confocal imaging revealed colocalization of complement factors with astroglial, microglial, neuronal, and abnormal cells in various patterns.SIGNIFICANCE: Our results demonstrate that the prominent activation of the complement pathway represents a common pathological hallmark of TSC and FCD2B, suggesting that complement overactivation may play a role in these mTORopathies.",
keywords = "complement, cortical development, epilepsy, focal cortical dysplasia, inflammation, tuberous sclerosis complex",
author = "Victoria-Elisabeth Gruber and Luinenburg, \{Mark J\} and Katrin Colleselli and Verena Endmayr and Anink, \{Jasper J\} and Zimmer, \{Till S\} and Floor Jansen and Peter Gosselaar and Roland Coras and Theresa Scholl and Ingmar Blumcke and Jos{\'e} Pimentel and Hainfellner, \{Johannes A\} and Romana H{\"o}ftberger and Karl R{\"o}ssler and Martha Feucht and \{van Scheppingen\}, Jackelien and Eleonora Aronica and Angelika M{\"u}hlebner",
note = "Funding Information: V.‐E.G. was funded by a grant of the Austrian Epilepsy Society dedicated to M.F. and by the German Tuberous Sclerosis Association (T.S., V.‐E.G.). The research leading to these results has also received funding from the European Union's Seventh Framework Program (FP7/2007‐2013) under grant agreement 602391 (EPISTOP; E.A., M.F., A.M., T.S.); the Dutch Epilepsy Foundation (project number 2020‐02; A.M., M.J.L., J.v.S.); the ZonMw Translational Research Program (95105004); and the European Union's Horizon 2020 WIDESPREAD‐05‐2020{\textendash}Twinning, EpiEpiNet (grant agreement 952455; E.A.). Funding Information: V.-E.G. was funded by a grant of the Austrian Epilepsy Society dedicated to M.F. and by the German Tuberous Sclerosis Association (T.S., V.-E.G.). The research leading to these results has also received funding from the European Union's Seventh Framework Program (FP7/2007-2013) under grant agreement 602391 (EPISTOP; E.A., M.F., A.M., T.S.); the Dutch Epilepsy Foundation (project number 2020-02; A.M., M.J.L., J.v.S.); the ZonMw Translational Research Program (95105004); and the European Union's Horizon 2020?WIDESPREAD-05-2020?Twinning, EpiEpiNet (grant agreement 952455; E.A.). The authors thank the team at the Epilepsy Monitoring Unit at the Department of Pediatrics at the Medical University of Vienna for their support in preparing clinical data and the neuropathology team at the Division of Neuropathology and Neurochemistry, Department of Neurology at the Medical University of Vienna for adequate processing and storage of tissue. The authors would also like to thank all members of the TSC brain bank for their cooperation (Service d' Anatomie Pathologique, CHI de Creteil and Inserm U676, Hospital Robert Debre, Paris, France: H. Adle-Biassette; Department of Pediatrics/Institute of Neurology/Department of Neurosurgery, Medical University of Vienna, Vienna, Austria: T. Czech; Department of Neuropathology, John Radcliffe Hospital, Oxford, UK: C. Kennard; Department of Anatomic Pathology Sciences, Universit? Sapienza, Rome, Italy: M. M. Antonelli, F. Giangaspero; Institute of Neuropathology, Westf?lische Wilhelms-Universit?t M?nster, M?nster, Germany: W. Paulus; Department of Neuropathology, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal: J. Pimentel; Department of Human Pathology and Oncology, University of Florence and Division of Neurosurgery, Anna Meyer Pediatric Hospital, Florence, Italy: A. M. Buccoliero, F. Giordano). Publisher Copyright: {\textcopyright} 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.",
year = "2022",
month = feb,
doi = "10.1111/epi.17139",
language = "English",
volume = "63",
pages = "364--374",
journal = "Epilepsia",
issn = "0013-9580",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "2",
}