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| Title | In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment. |
|---|---|
| Journal, issue, pages | Cell, Vol. 172, Issue 4, Page 696-705.e12, Year 2018 |
| Publish date | Feb 8, 2018 |
 Authors | Qiang Guo / Carina Lehmer / Antonio Martínez-Sánchez / Till Rudack / Florian Beck / Hannelore Hartmann / Manuela Pérez-Berlanga / Frédéric Frottin / Mark S Hipp / F Ulrich Hartl / Dieter Edbauer / Wolfgang Baumeister / Rubén Fernández-Busnadiego /   |
| PubMed 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- ...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. |
 External links | Cell / PubMed:29398115 / PubMed Central |
| Methods | EM (subtomogram averaging) / EM (tomography) |
| Resolution | 11.8 - 17.1 Å |
| Structure data | EMDB-3913, PDB-6epc: EMDB-3914, PDB-6epd: EMDB-3915, PDB-6epe: EMDB-3916, PDB-6epf:  EMDB-3917:  EMDB-4191: |
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 Keywords |  HYDROLASE / UPS / Ground state / Neuron degeneration / Substrate processing state |
