Für den Inhalt der Angaben zeichnet die Projektleitung verantwortlich.
This project is one of the five winners of the call 2013 «Rare Diseases - New Approaches».
Project partners: University of Geneva, Switzerland; University Hospital Geneva, Switzerland; University Erlangen, Germany
Förderbeitrag: CHF 490'000
Dauer: 04.2014 - 05.2018
Handlungsfeld: Rare Diseases, 2009 - 2014
Prof. Dr. Doron Merkler
University of Geneva Medical School CMU
Division of Clinical Pathology, Department of pathology and Immunology
1, rue Michel Servet
1211 Genève (Schweiz)
- doron.merkler@unige. ch
Rasmussen Encephalitis (RE) is a rare but often devastating inflammatory disease of the central nervous system (CNS) that typically starts in young children. The disease is characterized by epileptic seizures that are refractory to antiepileptic drugs and patients frequently develop an intellectual decline, loss of speech and finally hemiparesis. Currently there is no pharmacological curative treatment available and surgical resection of the affected hemisphere is frequently necessary to control seizures and halt neurological decline.
The exact cause of RE is still poorly understood but several lines of evidence suggest that cytotoxic T cells (CTLs) attacking neurons are crucially involved in the pathogenesis.
Our project shed novel insights into the involved molecular mechanisms that drive neuronal alterations in RE and its related animal model.
Was ist das Besondere an diesem Projekt?
For this project, we used a well-defined in vivo experimental model system that recreates key histopathological hallmarks observed in human RE patients. Thereby we could profile the translatome (e.g. the translated messenger RNA) in neurons that are exposed to a CTL attack. In addition, we applied a technology of multiplexed immunohistochemical stainings in experimental model system and human RE biopsies. This approach allowed us to elucidate neuronal-induced signaling pathway in spatial association with inflammatory infiltrates of the inflamed CNS. Furthermore, computer-assisted image analyses were equally applied on human cases of RE brain specimens. By this approach we could validate our experimental findings in the human disease condition. Our study provided novel insights into the fairly understood molecular underpinnings of RE and opens the basic for potentially promising new therapeutic approaches that could be of benefit for RE patients.
We have dissected in detail the involved signaling pathways that are induced in neurons following an attacked by cytotoxic lymphocytes. Molecular pathway analysis showed the contribution of different signaling pathways acting in neurons during disease manifestation. We further tested the functional implication of identified pathways for disease manifestation using gene-targeted knock out approaches. Our study identified the neuronal-induced genes that are key for neuronal degeneration and disease manifestation, that could also be successfully blocked by pharmacological interventions in vivo. The identified pathways could serve also as potentially suitable therapeutic targets for therapeutic interventions in RE patients.
In parallel to the experimental model system, we perform multiplex in situ analysis that takes into consideration the spatial association of different cell subsets and activated molecular pathways on human brain biopsies from RE patients. With this approach, we visualized key signaling events that are induced in human neurons. These analyses further allowed us to corroborate key activated pathways obtained in the experimental system and showed good correlation with neuronal alterations and clinical manifestations. Altogether, these results helped us to identify in situ biomarkers that could also serve to improve diagnostic precision and may be useful for therapeutic decisions in RE patient.
Selection of publications that paved the way to this project:
Kreutzfeldt M, Bergthaler A, Fernandez M, Brück W, Steinbach K, Vorm M, Coras R, Blümcke I, Bonilla WV, Fleige A, Forman R, Müller W, Becher B, Misgeld T, Kerschensteiner M, Pinschewer DD, Merkler D (2013). Neuroprotective intervention by interferon- blockade prevents CD8+ T cell-mediated dendrite and synapse loss. J Exp Med. 2013 Sep 23;210(10):2087-103;
Pinschewer DD, Schedensack M, Bergthaler A, Horvath E, Brück W, Löhning M, Merkler D (2010). T cells can mediate viral clearance from ependyma but not from brain parenchyma in a major histocompatibility class I- and perforin-independent manner. Brain. 2010 Apr;133(Pt 4):1054-66;
Merkler D, Horvath E, Bruck W, Zinkernagel RM, Del la Torre JC, Pinschewer DD (2006). J Clin Invest. 2006 May;116(5):1254-63. Epub 2006 Apr 6. "Viral déjà vu" elicits organ-specific immune disease independent of reactivity to self.
Am Projekt beteiligte Personen
Letzte Aktualisierung dieser Projektdarstellung 27.09.2018