Journal
CELL
Volume 172, Issue 4, Pages 696-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.12.030
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Funding
- EMBO [EMBO ALTF 73-2015]
- Alexander von Humboldt Foundation
- Seneca Foundation
- European Commission [FP7 GA ERC-2012-SyG_318987-ToPAG, FP7 GA ERC-2013-CoG_617198 DPR-MODELS]
- German Science Foundation (Excellence Cluster Center for Integrated Protein Science Munich [CIPSM])
- Munich Cluster for Systems Neurology (SyNergy) [SFB-1035]
- NOMIS Foundation
- Helmholtz Association
- NIH (Center for Macromolecular Modeling and Bioinformatics) [9P41GM104601]
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Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neuro-degenerative diseases. Here, we address the elusive link between these phenomena by employing cryo-electron tomography to dissect the molecular architecture of protein aggregates within intact neurons at high resolution. We focus on the poly-Gly-Ala (poly-GA) aggregates resulting from aberrant translation of an expanded GGGGCC repeat in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. We find that poly-GA aggregates consist of densely packed twisted ribbons that recruit numerous 26S proteasome complexes, while other macromolecules are largely excluded. Proximity to poly-GA ribbons stabilizes a transient substrate-processing conformation of the 26S proteasome, suggesting stalled degradation. Thus, poly-GA aggregates may compromise neuronal proteostasis by driving the accumulation and functional impairment of a large fraction of cellular proteasomes.
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