Targeting protein homeostasis in sporadic inclusion body myositis

Ahmed, Mhoriam; Machado, Pedro; Miller, A.; Spicer, Charlotte; Herbelin, Laura; He, Jia; Noel, Janelle; Wang, Yunxia; McVey, April; Pasnoor, Mamatha; Gallagher, Philip M.; Statland, Jeffrey; Lu, Ching‐Hua; Kalmár, Bernadett; Brady, Stefen; Sethi, Huma; Samandouras, George; Parton, Matt; Holton, Janice L.; Weston, Anne; Collinson, Lucy M.; Taylor, J. Paul; Schiavo, Giampietro; Hanna, Michael G.; Barohn, Richard J.; Dimachkie, Mazen M.; Greensmith, Linda

doi:10.1126/scitranslmed.aad4583

Cited by 107 publications

(90 citation statements)

References 57 publications

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“…Protein homeostasis or “proteostasis” likely plays an important role in sIBM pathogenesis and is thus a tractable therapeutic target. 30 Our study reveals that several new chaperone components may be relevant and refine therapeutic strategies. Small heat shock proteins and other molecular chaperones are of particular interest since they facilitate proper protein folding and degradation of misfolded and aggregated proteins.…”

Section: Discussionmentioning

confidence: 85%

Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis

Güttsches

Brady

Krause

et al. 2017

Annals of Neurology

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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.

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Section: Discussionmentioning

confidence: 85%

Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis

Güttsches

Brady

Krause

et al. 2017

Annals of Neurology

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“…In this study [60] Arimoclomol was found to ameliorate s-IBM-like pathology both in vitro , in primary rodent muscle cells induced to develop either the degenerative or the inflammatory features of s-IBM, as well as in vivo , in mice over-expressing mutant VCP (p97 in mouse) which have a phenotypic spectrum that includes inclusion body myopathy. In addition, in a randomized, double blind, placebo-controlled, proof-of-concept trial of Arimoclomol for the treatment of s-IBM in human patients, Arimoclomol was found to be safe and well tolerated.…”

Section: Session 4 – Vcp Function and Dysfunction: Pre-clinical Stmentioning

confidence: 99%

215th ENMC International Workshop VCP-related multi-system proteinopathy (IBMPFD) 13–15 November 2015, Heemskerk, The Netherlands

Evangelista

Weihl

Kimonis

et al. 2016

Neuromuscular Disorders

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“…The most prominent mechanistic hypothesis for IBM myodegeneration implicates abnormal proteostasis, as many proteins associated with neurodegenerative disease (e.g. TDP-43, p62, amyloid-β, and αβ-crystallin) are reported to aggregate in the cytosol of IBM-affected myofibers [2, 12, 23]. Ca 2+ dysregulation contributes to abnormal proteostasis by promoting mitochondrial reactive oxygen species (ROS) production and perturbing protein folding in the endoplasmic reticulum (ER) lumen [18, 31].…”

Section: Introductionmentioning

confidence: 99%

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

Amici

Pinal‐Fernandez

Mázala

et al. 2017

acta neuropathol commun

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Sporadic inclusion body myositis (IBM) is the most common primary myopathy in the elderly, but its pathoetiology is still unclear. Perturbed myocellular calcium (Ca2+) homeostasis can exacerbate many of the factors proposed to mediate muscle degeneration in IBM, such as mitochondrial dysfunction, protein aggregation, and endoplasmic reticulum stress. Ca2+ dysregulation may plausibly be initiated in IBM by immune-mediated membrane damage and/or abnormally accumulating proteins, but no studies to date have investigated Ca2+ regulation in IBM patients. We first investigated protein expression via immunoblot in muscle biopsies from IBM, dermatomyositis, and non-myositis control patients, identifying several differentially expressed Ca2+-regulatory proteins in IBM. Next, we investigated the Ca2+-signaling transcriptome by RNA-seq, finding 54 of 183 (29.5%) genes from an unbiased list differentially expressed in IBM vs. controls. Using an established statistical approach to relate genes with causal transcription networks, Ca2+ abundance was considered a significant upstream regulator of observed whole-transcriptome changes. Post-hoc analyses of Ca2+-regulatory mRNA and protein data indicated a lower protein to transcript ratio in IBM vs. controls, which we hypothesized may relate to increased Ca2+-dependent proteolysis and decreased protein translation. Supporting this hypothesis, we observed robust (4-fold) elevation in the autolytic activation of a Ca2+-activated protease, calpain-1, as well as increased signaling for translational attenuation (eIF2α phosphorylation) downstream of the unfolded protein response. Finally, in IBM samples we observed mRNA and protein under-expression of calpain-3, the skeletal muscle-specific calpain, which broadly supports proper Ca2+ homeostasis. Together, these data provide novel insight into mechanisms by which intracellular Ca2+ regulation is perturbed in IBM and offer evidence of pathological downstream effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0427-7) contains supplementary material, which is available to authorized users.

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Targeting protein homeostasis in sporadic inclusion body myositis

Cited by 107 publications

References 57 publications

Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis

Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis

215th ENMC International Workshop VCP-related multi-system proteinopathy (IBMPFD) 13–15 November 2015, Heemskerk, The Netherlands

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

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