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Bassoon proteinopathy drives neurodegeneration in multiple sclerosis

Schattling, Benjamin, Engler, Jan Broder, Volkmann, Constantin, Rothammer, Nicola, Woo, Marcel S., Petersen, Meike, Winkler, Iris, Kaufmann, Max, Rosenkranz, Sina C., Fejtova, Anna, Thomas, Ulrich, Bose, Aparajita, Bauer, Simone, Träger, Simone, Miller, Katharine K., Brück, Wolfgang, Duncan, Kent E., Salinas, Gabriela, Soba, Peter, Gundelfinger, Eckart D., Merkler, Doron, Friese, Manuel A.·2019·Nature Neuroscience
DOI 10.1038/s41593-019-0385-4
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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.

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Metadata

Authors
Schattling, B., Engler, J. B., Volkmann, C., Rothammer, N., Woo, M. S., Petersen, M., Winkler, I., Kaufmann, M., Rosenkranz, S. C., Fejtova, A., Thomas, U., Bose, A., Bauer, S., Träger, S., Miller, K. K., Brück, W., Duncan, K. E., Salinas, G., Soba, P., Gundelfinger, E. D., Merkler, D., & Friese, M. A.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2019-04-22
Volume
22
Issue
6
Pages
887-896
ISSN
  • 1097-6256
  • 1546-1726
DOI
10.1038/s41593-019-0385-4
Cited by
86
References
16
Language
en
Licence
www.springer.com/tdm (tdm)

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