UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers

Kedia, N; Arhzaouy, K; Pittman, SK; Sun, Y; Batchelor, M; Weihl, CC; Bieschke, J; (2019) Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers. Proceedings of the National Academy of Sciences of the United States of America , 116 (34) pp. 16835-16840. 10.1073/pnas.1908263116. Green open access

[thumbnail of 16835.full.pdf]
Preview
Text
16835.full.pdf - Published Version

Download (1MB) | Preview

Abstract

Desmin-associated myofibrillar myopathy (MFM) has pathologic similarities to neurodegeneration-associated protein aggregate diseases. Desmin is an abundant muscle-specific intermediate filament, and disease mutations lead to its aggregation in cells, animals, and patients. We reasoned that similar to neurodegeneration-associated proteins, desmin itself may form amyloid. Desmin peptides corresponding to putative amyloidogenic regions formed seeding-competent amyloid fibrils. Amyloid formation was increased when disease-associated mutations were made within the peptide, and this conversion was inhibited by the anti-amyloid compound epigallocatechin-gallate. Moreover, a purified desmin fragment (aa 117 to 348) containing both amyloidogenic regions formed amyloid fibrils under physiologic conditions. Desmin fragment-derived amyloid coaggregated with full-length desmin and was able to template its conversion into fibrils in vitro. Desmin amyloids were cytotoxic to myotubes and disrupted their myofibril organization compared with desmin monomer or other nondesmin amyloids. Finally, desmin fragment amyloid persisted when introduced into mouse skeletal muscle. These data suggest that desmin forms seeding-competent amyloid that is toxic to myofibers. Moreover, small molecules known to interfere with amyloid formation and propagation may have therapeutic potential in MFM.

Type: Article
Title: Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1908263116
Publisher version: https://doi.org/10.1073/pnas.1908263116
Language: English
Additional information: Copyright © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/).
Keywords: amyloid, desmin, myofibrillar myopathy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10080881
Downloads since deposit
59Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item