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RG Höltje: Autoimmune diseases of the nervous system

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Autoimmune diseases of the nervous system

In close cooperation with neurologically oriented clinics and institutes, the occurrence and underlying mechanisms of various autoimmune-mediated diseases of the nervous system are examined.

Autoimmune diseases of the CNS have received considerable attention in recent years due to the identification of a growing number of neuronal autoantigens and the characterization of corresponding clinical disease entities. For example, antibodies against the N-methyl-D-aspartate receptor (NMDAR) are associated with a severe form of limbic encephalitis that mainly affects younger women. In addition, NMDAR antibodies may also contribute to cognitive slowing in the elderly, expanding current views of the molecular events underlying at least a subset of neurodegenerative diseases. These findings require an in-depth characterization of the pathogenic mechanisms of antibody-mediated neuronal autoimmunity and the associated clinical pathology, which represents a classic example of translational medicine ("from synapse to symptom" and "from symptom to synapse"). In this context, we were able to characterize pathogenic effects of antibodies in anti-DPPX encephalitis, an antibody-mediated disease identified in 2013 that affects both the central and the enteric nervous system. Anti-DPPX sera caused hyperexcitability of enteric nervous system neurons and decreased DPPX expression in hippocampal neuron membranes, reflecting the clinical phenotype of patients with anti-DPPX encephalitis.

Furthermore, we identified the vesicle-associated protein synapsin (I and II) as a previously undescribed target of autoantibodies of the IgA and IgG subclasses in a patient with limbic encephalitis. In a follow-up study, we investigated the prevalence of synapsin autoantibodies in a multicenter study analyzing sera from patients with various neurological disorders. These included a) encephalitis, some associated with other anti-neuronal antibodies, b) multiple sclerosis (MS) or clinically isolated syndrome (CIS), and c) psychiatric cases of psychotic, bipolar or depressive disorders.

Synapsin autoantibodies of the IgG subtype were found in approximately 6% of patients but not in healthy controls.In a study on SARS-CoV-2 antibodies, autoimmunity against brain structures, including blood vessels, was demonstrated for a subpopulation of antibodies directed against the viral spike protein.

The study of the occurrence of autoimmune reactive antibodies against cerebral vessels in the context of encephalitis and autoimmunity in connection with dementia is currently the focus of the work group.

Clostridial C3 proteins as tools to foster neuronal regeneration

C3 proteins - often referred to as C3 exoenzymes or C3 transferases - form a family of seven known ADP-ribosyltransferases from different bacterial strains. All members of this protein family selectively ADP-ribosylate the small GTP-binding proteins RhoA, B, C and thus inhibit downstream signaling pathways, which is why they have been used as tools to study Rho-dependent processes since their discovery. Rho proteins are the key regulators of the cytoskeleton of eukaryotic cells. During enzymatic inactivation, ADP-ribose of the co-substrate nicotinamide adenine dinucleotide (NAD+) is transferred to asparagine at position 41 of Rho. Functionally, this results in Rho being inactivated. In recent years, we and other research groups have also been able to demonstrate non-enzymatic interactions or cellular effects for some C3 proteins. In work on hippocampal culture systems and in vivo regeneration models after experimental spinal cord lesions in mice, we were able to show for the first time that C3bot has a neurotrophic activity that occurs completely independently of the enzymatic activity.

As described, the transferase C3bot produced by Clostridium botulinum and peptides derived from it cause accelerated growth and an increased degree of branching in axons and dendrites. The intermediate filament protein vimentin appears to be an extracellular receptor for C3bot. In addition to vimentin, other membrane surface structures (carbohydrates, lipids) are important for binding and uptake of C3bot. Using a vimentin knock-out (mouse) model, we were able to confirm the role of vimentin in the axonotrophic effects of C3bot. By using the vimentin knock-out model, further structures/proteins involved in binding and uptake as well as in intracellular effects should be identified. In this context, the ß1-integrin subunit was characterized as an additional binding partner. Recently, our group could further show that vimentin binds to the plasma membrane of neurons via exosomal release from astrocytes and thus promotes the neurotrophic effect of C3bot.



Prof. Dr. Harald Prüß

German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany. Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, Germany.

Prof Dr. Ingo Just

PD Dr. Astrid Rohrbeck

Institute of Toxicology, Hannover Medical School (MHH), Germany

Prof. Dr. Klemens Ruprecht

Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, Germany.

Prof. Dr. Fabio Benfenati

Istituto Italiano di Tecnologia | IIT · Center for Synaptic Neuroscience and Technology, Genova, Italy

Dr. Daniel Gitler

Ben-Gurion University of the Negev, Beersheba, Israel

PD Dr. Malgorzata Burek

Department of Anaesthesia and Critical Care, University Hospital Würzburg, Würzburg, Germany



Funding and Patents

Deutsche Forschungsgemeinschaft (German Research Council, DFG)

Work is supported by the DFG GZ HO 3249/2-1 in cooperation with the grant to Prof. Ingo Just GZ JU 231/5-1

"Neuro-regenerative C3bot peptides - characterization of uptake and signal transduction compared to C3bot enzyme"

Past Grants:

 "Molecular mechanisms of the neurotrophic  C. botulinum exoenzyme  action"  DFG  GZ AH 67/4-1, -2  



"Polypeptides and use therof for the treatment of traumatic or degenerative neuronal injury"

Aktenzeichen EP 107 120 75.0