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Free keywords:
DIPEPTIDE REPEAT PROTEIN; AMYOTROPHIC-LATERAL-SCLEROSIS; HUMAN 26S
PROTEASOME; HEXANUCLEOTIDE REPEAT; MOLECULAR-DYNAMICS; RNA FOCI;
CRYO-EM; CLINICOPATHOLOGICAL CORRELATIONS; FRONTOTEMPORAL DEMENTIA;
CRYOELECTRON TOMOGRAPHYBiochemistry & Molecular Biology; Cell Biology;
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.
