Academic Journal
Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons
| العنوان: | Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons |
|---|---|
| المؤلفون: | Riemenschneider, H., Guo, Q., Bader, J., Frottin, F., Farny, D., Kleinberger, G., Haass, C., Mann, M., Hartl, F., Baumeister, W., Hipp, M., Meissner, F., Fernandez-Busnadiego, R., Edbauer, D. |
| المصدر: | EMBO Reports |
| سنة النشر: | 2022 |
| المجموعة: | Max Planck Society: MPG.PuRe |
| الوصف: | Aggregation of the multifunctional RNA-binding protein TDP-43 defines large subgroups of amyotrophic lateral sclerosis and fronto-temporal dementia and correlates with neurodegeneration in both diseases. In disease, characteristic C-terminal fragments of similar to 25 kDa ("TDP-25") accumulate in cytoplasmic inclusions. Here, we analyze gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics, and functional assays. In neurons, cytoplasmic TDP-25 inclusions are amorphous, and photobleaching experiments reveal gel-like biophysical properties that are less dynamic than nuclear TDP-43. Compared with full-length TDP-43, the TDP-25 interactome is depleted of low-complexity domain proteins. TDP-25 inclusions are enriched in 265 proteasomes adopting exclusively substrate-processing conformations, suggesting that inclusions sequester proteasomes, which are largely stalled and no longer undergo the cyclic conformational changes required for proteolytic activity. Reporter assays confirm that TDP-25 impairs proteostasis, and this inhibitory function is enhanced by ALS-causing TDP-43 mutations. These findings support a pathophysiological relevance of proteasome dysfunction in ALS/FTD. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | http://hdl.handle.net/21.11116/0000-000A-5F75-9 |
| الاتاحة: | http://hdl.handle.net/21.11116/0000-000A-5F75-9 |
| رقم الانضمام: | edsbas.C31D96D2 |
| قاعدة البيانات: | BASE |
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