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| Status |
Public on Apr 03, 2019 |
| Title |
Bassoon proteinopathy drives neurodegeneration in multiple sclerosis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
|
| Summary |
During the course of multiple sclerosis (MS), inflammatory insults drive neuro-axonal loss and disability progression. However, pathways that guide neurons toward survival or death during central nervous system (CNS) inflammation are largely unexplored. Here we show that somatic deposition of the presynaptic protein bassoon (Bsn) in inflamed neurons directly contributes to neurodegeneration in MS. By comparing neuron-specific RNA-seq of healthy mice to mice undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identified key components of neurodegenerative pathways, including reduced mitochondrial ATP synthesis and increased protein catabolism. These changes were accompanied by neuronal induction and deposition of the intrinsically disordered protein Bsn in both EAE and in patients with MS. Somatic Bsn also accumulated in Bsn-overexpressing Neuro-2a (N2a) cells and single cell RNA-seq revealed dose-dependent repression of energy metabolism and induction of the unfolded protein response, reminiscent of our in vivo findings. Furthermore, Bsn overexpression in N2a cells or in Drosophila melanogaster neurons led to decreased survival and shortened lifespan, respectively. Conversely, genetic disruption of Bsn in mice was neuroprotective, with reduced neuro-axonal injury and clinical disability during EAE, establishing a toxic gain-of-function of Bsn during CNS inflammation. Our study provides systemic insights into neuronal responses to inflammation and identifies protein accumulation as a generic pathomechanism uniting primary and inflammatory neurodegeneration. Moreover, it offers a new explanation and possible treatment strategy to halt disability progression in MS, irrespective of immunotherapies.
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| Overall design |
Refer to individual Series
|
| |
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| Citation(s) |
31011226, 39145444 |
| |
| Submission date |
Oct 12, 2017 |
| Last update date |
Sep 12, 2024 |
| Contact name |
Manuel A Friese |
| E-mail(s) |
manuel.friese@zmnh.uni-hamburg.de
|
| Organization name |
Universitätsklinikum Hamburg-Eppendorf
|
| Department |
Institut für Neuroimmunologie und Multiple Sklerose
|
| Street address |
Falkenried 94
|
| City |
Hamburg |
| ZIP/Postal code |
20251 |
| Country |
Germany |
| |
|
| Platforms (2) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
|
| Samples (21)
|
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| This SuperSeries is composed of the following SubSeries: |
| GSE104897 |
TRAP-seq of spinal cord motor neurons in EAE versus healthy mice |
| GSE104898 |
Drop-seq of N2a cells transfected with Bsn |
|
| Relations |
| BioProject |
PRJNA414103 |
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