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Cell. 2018 Feb 8;172(4):696-705.e12. doi: 10.1016/j.cell.2017.12.030. Epub 2018 Feb 1.

In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment.

Author information

1
Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
2
German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
3
Department of Biophysics, Ruhr University Bochum, 44780 Bochum, Germany; NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA.
4
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
5
Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany; Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
6
German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany; Ludwig-Maximilians University Munich, 81377 Munich, Germany. Electronic address: dieter.edbauer@dzne.de.
7
Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany. Electronic address: baumeist@biochem.mpg.de.
8
Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany. Electronic address: ruben@biochem.mpg.de.

Abstract

Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative 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.

KEYWORDS:

ALS; FTD; UPS; cryo-EM; cryo-ET; cryo-FIB; cryoelectron microscopy; dipeptide-repeat proteins

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