In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment.
Cell. 2018 Feb 8;172(4):696-705.e12. doi: 10.1016/j.cell.2017.12.030. Epub 2018 Feb 1.
|Authors/Editors:||Guo Q, Lehmer C, Martínez-Sánchez A, Rudack T, Beck F, Hartmann H, Pérez-Berlanga M, Frottin F, Hipp MS, Hartl FU, Edbauer D, Baumeister W, Fernández-Busnadiego R.|
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.