Molecular & translational Neuroimmunology
Our research focus on inflammatory neurodegeneration and mechanisms of disturbed neuroregeneration including almost all cell types of the central nervous system: neurons, oligodendrocytes, astrocytes, and microglia (Fig. 1). Our research projects are related to all of these cell types. The Molecular Neurology Research Group is divided into a clinical (located at the NMR clinic) and a basic science part (located at the Life Science Center). This enables us to combine these two areas of research leading to unique bi-translational possibilities in understanding the molecular mechanism of several therapeutic approaches of neuroimmunological diseases. One the one hand we investigate common neurological diseases, especially multiple sclerosis (Aktas et al. Trends Neurosci 2010) but on the other hand also rare autoimmune diseases such as neuromyelitis optica (NMO; Devic syndrome) and Susac syndrome
Experimental basic research
Thiol-Redox Research in Molecular Neurology (Carsten Berndt)
The essential role of redox regulation in health and disease is undisputed, including developmental and damage processes in the brain. Reactive oxygen species (ROS) have long been considered to be only deleterious by damaging DNA, proteins, and lipids. Meanwhile, ROS were uncovered as important second messengers for specific signaling events via reversible oxidative posttranslational thiol modifications. Adequate reaction velocity and appropriate specificity for regulation of these modifications is contributed by enzymes, especially by oxidoreductases of the thioredoxin family. Together with the Karolinska Institute in Stockholm we identified specific redox regulated pathways essential for embryonic development (Bräutigam et al., Proc Natl Acad Sci USA 2011 , Bräutigam et al., Proc Natl Acad Sci USA 2013 , Berndt et al., Redox Biol, 2014 ). We are aiming in the identification of specific redox signaling events, e.g. based on the characterized pathways during embryonic development, on regulating several aspects of damages of the central nervous system: de- and remyelination, neuronal damage and axonal regeneration, as well as formation of an astroglial scar (Fig. 2).
Additional informations including publications can be found here: www.carsten-berndt.de
Neuroimmune interactions in adult neurogenesis (Tim Prozorovski)
Regeneration and repair of the damaged CNS tissue is particularly challenging. Neural stem/progenitor cells has a regenerative capacity, however, the efficiency is severely limited and declines with age. Our major focus is the identification and validation of molecular targets that may allow the specific recruitment of endogenous progenitors for tissue repair. To address this question, we are investigating the alteration in the activity of signalling pathways relevant for adult glio- and neurogenesis in pathological conditions associated with neuroinflammation, metabolic disorders or healthy ageing. Our current work has revealed that the histone deacetylase silent information regulator 1 (Sirt1) serves as a sensor for the alterations in redox state in neural stem/progenitor cells, and affect their neuronal fate via modulation of basic helix loop helix (bHLH) transcription factors Hes1 and Mash1 (Prozorovski et al., Nat Cell Biol 2008; 10:385). We are currently exploring the the action of other sirtuin genes (Sirt3 and Sirt6), implicated in regulation of lifespan, in neural stem cell maintenance and differentiation. We also found that a CNS antigen-specific immune response leads to an aberrant differentiation of neuronal precursors in the hippocampus associated with dysbalance of Wnt and Notch signaling pathways (Huehnchen et al., Glia 2011; 59(1):132). Our findings suggest that, despite the proliferative response of the neuronal precursors, the failure to generate new neurons may be a contributing factor to the impaired cognitive deficit in patients with autoimmune disorder of the CNS, such as multiple sclerosis (Prozorovski et al., Biochim Biophys Acta 2015) .
Clinical and experimental immunology (Jens Ingwersen)
On the border between clinical and basic science and in close connection with Timur Prozorovski, the murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) is applied to investigate molecular mechanisms of drugs on the immunological aspects of the disease (Ingwersen et al., Ann Clin Transl Neurol 2015; Kocur et al., Acta Neuropath Commun 2015, Huehnchen et al., Glia 2011). Moreover, using this disease model, we aim in the identification and characterization of new player important for development and progression of the disease. Here, we mainly focus on the role of microRNA in mouse and man and the regulation of the adenosine metabolism in CNS and in the immune system during MS and EAE (in cooperation with Research Center Jülich) (Fig. 3).
Rare diseases: Neuromyelitis optica and Susac syndrome (Marius Ringelstein)
Neuromyelitis optica (NMO, Devic syndrome) is increasingly recognized as autoimmune central nervous system disorder with a pathogenesis distinct from MS. We contributed to the characterization of an auto-antibody against the astrocytic water channel aquaporin-4 (AQP4) as a new biomarker for NMO (Paul et al., PLOS Med), that was the major breakthrough allowing this discrimination: whereas this antibody is not present in MS patients, it is present in majority of NMO patients. The foundation of the NMO study group (NEMOS) aims for the synergistic investigation of this rare disease and the improved health care of patients. Quite a lot publications of NEMOS demonstrate success of this german network, e.g. Jarius et al., J Neuroinflammation 2012 Kleiter et al., Arch Neurol 2012 Ringelstein et al., Mult Scler 201 Trebst et al., J Neurol 2014 Krumbholz et al., J Neurol 2015). One focus is the investigation of effective therapies. Recently were were able to demonstrate that blockage of the interleukin-6 signaling pathway stabilizes disease progression (Harmel et al., BMC Neurol 2014 Ringelstein et al., JAMA Neurol 2015 ). Another, even more rare autoimmune disease than NMO, is the Susac syndrome (SuS). This disease is characterized by encephalopathy, branch retinal artery occlusions, and hearing loss (Dörr et al., Nat Rev Neurol 2013 Dörr et al., J Alzheimers Dis 2014). Within the European Susac consortium (EuSac) we are currently working on the further characterization of this disease: we investigated i) the role of the anti-endothelial cell antibody (AECA) during pathophysiology of SuS (Jarius et al., J Neuroinflammation 2014), ii) new diagnostic tools, e.g. the optic coherence tomography (OCT) (Brandt et al., PLOS ONE 2012 Ringelstein et al., Neurology, in press), leading to the development and establishment of new diagnostic criteria.
For financial support of the Molecular Neurology Research Group we thank:
name (alphabetical order)
|Aktas, Orhan||Univ.-Prof. Dr. med., group leader Molecular Neurology Research Groupfirstname.lastname@example.org|
|Bayer, Mary||technician & lab email@example.com|
|Berndt, Carsten||Dr. rer nat., group leader thiol redox firstname.lastname@example.org|
|Bosch, Bastian||Master student (thiol redox research)||Bastian.Bosch@uni-duesseldorf.de|
|Gierisch, Matthias||MD student (thiol redox research)||email@example.com|
|Graf, Jonas||MD student (immunology)||firstname.lastname@example.org|
|Harmel, Jens||clinician (rare diseases)||email@example.com|
|Hildebrandt, Thomas||PhD student (thiol redox research)||Thomas.Hildebrandt@med.uni-duesseldorf.de|
|Ingwersen, Jens||MD, clinician, group leader clinical and experimental firstname.lastname@example.org|
|Lepka, Klaudia||PhD student (thiol redox research)||Klaudia.Lepka@uni-duesseldorf.de|
|Peters, Corinna||coordination of clinical email@example.com|
|Prozorovskiy, Timur||Dr. rer.nat., group leader sirtuin firstname.lastname@example.org|
|Ringelstein, Marius||Dr. med., clinician, group leader rare email@example.com|
|Schaberg, Elena||Master student (thiol redox research)||Elena.Schaberg@uni-duesseldorf.de|
|Seiwert, Helga||office and lab firstname.lastname@example.org|