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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 (2018): In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment. In: Cell, Vol. 172, No. 4: pp. 696-705
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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.