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

Guo, Q., Lehmer, C., Martinez Sanchez, A., Rudack, T., Beck, F., Hartmann, H., et al. (2018). In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment. Cell, 172(4), 696-705.e12. doi:10.1016/j.cell.2017.12.030.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-AF4B-8 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-AF4C-7
Genre: Journal Article

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https://doi.org/10.1016/j.cell.2017.12.030 (Publisher version)
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 Creators:
Guo, Qiang1, Author              
Lehmer, Carina2, Author
Martinez Sanchez, Antonio1, Author              
Rudack, Till2, Author
Beck, Florian1, Author              
Hartmann, Hannelore2, Author
Perez-Berlanga, Manuela3, Author              
Frottin, Frederic3, Author              
Hipp, Mark S.3, Author              
Hartl, F. Ulrich3, Author              
Edbauer, Dieter2, Author
Baumeister, Wolfgang1, Author              
Fernandez-Busnadiego, Ruben1, Author              
Affiliations:
1Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              
2external, ou_persistent22              
3Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Free keywords: DIPEPTIDE REPEAT PROTEIN; AMYOTROPHIC-LATERAL-SCLEROSIS; HUMAN 26S PROTEASOME; HEXANUCLEOTIDE REPEAT; MOLECULAR-DYNAMICS; RNA FOCI; CRYO-EM; CLINICOPATHOLOGICAL CORRELATIONS; FRONTOTEMPORAL DEMENTIA; CRYOELECTRON TOMOGRAPHYBiochemistry & Molecular Biology; Cell Biology;
 Abstract: 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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Language(s): eng - English
 Dates: 2018
 Publication Status: Published in print
 Pages: 22
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Degree: -

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Project name : FP7 GA ERC-2012-SyG_318987–ToPAG FP7 GA ERC-2013-CoG_617198 DPR-MODELS
Grant ID : 318987
Funding program : Funding Programme 7 (FP7)
Funding organization : European Commission (EC)

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Title: Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 172 (4) Sequence Number: - Start / End Page: 696 - 705.e12 Identifier: ISSN: 0092-8674
CoNE: https://pure.mpg.de/cone/journals/resource/954925463183