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Nat Neurosci. 2019 Apr 22. doi: 10.1038/s41593-019-0385-4. [Epub ahead of print]

Bassoon proteinopathy drives neurodegeneration in multiple sclerosis.

Author information

1
Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
2
Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
3
Leibniz-Institute für Neurobiologie, Magdeburg, Germany.
4
Psychiatrische und Psychotherapeutische Klinik, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
5
Institut für Neuropathologie, Universitätsmedizin Göttingen, Georg-August-Universität Göttingen, Göttingen, Germany.
6
Transkriptomanalyselabor, Institut für Entwicklungsbiochemie, Universitätsmedizin Göttingen, Georg-August-Universität Göttingen, Göttingen, Germany.
7
Center for Behavioral Brain Sciences and Medical Faculty, Otto von Guericke Universität, Magdeburg, Germany.
8
Department of Pathology and Immunology, Service of Clinical Pathology, Geneva Faculty of Medicine, Geneva, Switzerland.
9
Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. manuel.friese@zmnh.uni-hamburg.de.

Abstract

Multiple sclerosis (MS) is characterized by inflammatory insults that drive neuroaxonal injury. However, knowledge about neuron-intrinsic responses to inflammation is limited. By leveraging neuron-specific messenger RNA profiling, we found that neuroinflammation leads to induction and toxic accumulation of the synaptic protein bassoon (Bsn) in the neuronal somata of mice and patients with MS. Neuronal overexpression of Bsn in flies resulted in reduction of lifespan, while genetic disruption of Bsn protected mice from inflammation-induced neuroaxonal injury. Notably, pharmacological proteasome activation boosted the clearance of accumulated Bsn and enhanced neuronal survival. Our study demonstrates that neuroinflammation initiates toxic protein accumulation in neuronal somata and advocates proteasome activation as a potential remedy.

PMID:
31011226
DOI:
10.1038/s41593-019-0385-4

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