Güttsches, Anne-Katrin;
Brady, Stefen;
Krause, Kathryn;
Maerkens, Alexandra;
Uszkoreit, Julia;
Eisenacher, Martin;
Schreiner, Anj;
... Kley, Rudolf A; + view all
(2017)
Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis.
Annals of Neurology
, 81
(2)
pp. 227-239.
10.1002/ana.24847.
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Abstract
OBJECTIVE: Sporadic inclusion body myositis (sIBM) pathogenesis is unknown; however, rimmed vacuoles (RVs) are a constant feature. We propose to identify proteins that accumulate within RVs. METHODS: RVs and intact myofibers were laser microdissected from skeletal muscle of 18 sIBM patients and analyzed by a sensitive mass spectrometry approach using label-free spectral count-based relative protein quantification. Whole exome sequencing was performed on 62 sIBM patients. Immunofluorescence was performed on patient and mouse skeletal muscle. RESULTS: 213 proteins were enriched by >1.5X in RVs compared to controls and included proteins previously reported to accumulate in sIBM tissue or when mutated cause myopathies with RVs. Proteins associated with protein folding and autophagy were the largest group represented. One autophagic adaptor protein not previously identified in sIBM was FYCO1. Rare missense coding FYCO1 variants were present in 11.3% of sIBM patients compared with 2.6% of controls (p=0.003). FYCO1 co-localized at RVs with autophagic proteins such as MAP1LC3 and SQSTM1 in sIBM and other RV myopathies. One FYCO1 variant protein had reduced co-localization with MAP1LC3 when expressed in mouse muscle. INTERPRETATION: This study used an unbiased proteomic approach to identify RV proteins in sIBM that included a novel protein involved in sIBM pathogenesis. FYCO1 accumulates at RVs and rare missense variants in FYCO1 are overrepresented in sIBM patients. These FYCO1 variants may impair autophagic function leading to RV formation in sIBM patient muscle. FYCO1 functionally connects autophagic and endocytic pathways supporting the hypothesis that impaired endolysosmal degradation underlies the pathogenesis of sIBM.
| Type: | Article |
|---|---|
| Title: | Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/ana.24847 |
| Publisher version: | https://doi.org/10.1002/ana.24847 |
| Language: | English |
| Additional information: | Copyright © 2017 American Neurological Association. All rights reserved. This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at http://dx.doi.org/10.1002/ana.24847. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. |
| Keywords: | FYCO1, Sporadic inclusion body myositis, rimmed vacuoles |
| 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 Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1537311 |
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