1. In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment
- Author
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Hannelore Hartmann, Mark S. Hipp, Wolfgang Baumeister, Florian Beck, Qiang Guo, Till Rudack, Frédéric Frottin, Manuela Pérez-Berlanga, F. Ulrich Hartl, Rubén Fernández-Busnadiego, Antonio Martinez-Sanchez, Dieter Edbauer, and Carina Lehmer
- Subjects
0301 basic medicine ,In situ ,genetics [Proteasome Endopeptidase Complex] ,poly(glutamic acid-alanine) ,Protein aggregation ,Rats, Sprague-Dawley ,0302 clinical medicine ,C9orf72 ,analogs & derivatives [Alanine] ,pathology [Neurons] ,Amyotrophic lateral sclerosis ,genetics [Frontotemporal Dementia] ,Neurons ,Alanine ,Protein Stability ,Translation (biology) ,metabolism [Polyglutamic Acid] ,3. Good health ,Cell biology ,genetics [Amyotrophic Lateral Sclerosis] ,Polyglutamic Acid ,metabolism [C9orf72 Protein] ,metabolism [Neurons] ,Frontotemporal Dementia ,metabolism [Frontotemporal Dementia] ,ATP dependent 26S protease ,Frontotemporal dementia ,Proteasome Endopeptidase Complex ,genetics [Alanine] ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Protein Aggregates ,03 medical and health sciences ,medicine ,Animals ,Humans ,ddc:610 ,metabolism [Proteasome Endopeptidase Complex] ,pathology [Amyotrophic Lateral Sclerosis] ,Protein Structure, Quaternary ,metabolism [Alanine] ,genetics [C9orf72 Protein] ,C9orf72 Protein ,metabolism [Amyotrophic Lateral Sclerosis] ,Amyotrophic Lateral Sclerosis ,medicine.disease ,Rats ,genetics [Polyglutamic Acid] ,HEK293 Cells ,030104 developmental biology ,Proteostasis ,Proteasome ,Protein Biosynthesis ,pathology [Frontotemporal Dementia] ,030217 neurology & neurosurgery - 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.
- Published
- 2018