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

Guo, Qiang; Lehmer, Carina; Martinez Sanchez, Antonio; Rudack, Till; Beck, Florian; Hartmann, Hannelore; Perez-Berlanga, Manuela; Frottin, Frederic; Hipp, Mark S.; Hartl, F. Ulrich; Edbauer, Dieter; Baumeister, Wolfgang; Fernandez-Busnadiego, Ruben

doi:10.1016/j.cell.2017.12.030

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

MPS-Authors

/persons/resource/persons216754

Guo, Qiang
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons209032

Martinez Sanchez, Antonio
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons77726

Beck, Florian
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons205464

Perez-Berlanga, Manuela
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons188359

Frottin, Frederic
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons78111

Hipp, Mark S.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons78072

Hartl, F. Ulrich
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons77721

Baumeister, Wolfgang
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons77952

Fernandez-Busnadiego, Ruben
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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https://doi.org/10.1016/j.cell.2017.12.030
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Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-0000-AF4B-8

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.