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, and Rubén Fernández-Busnadiego.
In situ structure of neuronal C9orf72 poly-GA
aggregates reveals proteasome recruitment.
Cell, 172:696-705, 2018.
(PMC: PMC6035389)
GUO2018-TR
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.
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