Desmin mutations in the terminal consensus motif prevent synemin-desmin heteropolymer filament assembly

Chourbagi, Oussama; Bruston, Francine; Carinci, Marianna; Xue, Zhigang; Vicart, Patrick; Paulin, Denise; Agbulut, Onnik

doi:10.1016/j.yexcr.2011.01.013

Cited by 26 publications

(26 citation statements)

References 42 publications

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“…These results suggest that DesS46Y, DesS460I, and DesD399Y-associated layout mechanisms differ from one to another. This is consistent with results showing specific interactions in aggregates of some desmin mutants (DesE401K, DesR406W, DesE413K) with the IF synemin in contrast to some others (DesD399Y, DesS460I) [44]. …”

Section: Discussionsupporting

confidence: 92%

N-Acetyl-L-Cysteine Prevents Stress-Induced Desmin Aggregation in Cellular Models of Desminopathy

et al. 2013

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Mutations within the human desmin gene are responsible for a subcategory of myofibrillar myopathies called desminopathies. However, a single inherited mutation can produce different phenotypes within a family, suggesting that environmental factors influence disease states. Although several mouse models have been used to investigate organ-specific desminopathies, a more general mechanistic perspective is required to advance our knowledge toward patient treatment. To improve our understanding of disease pathology, we have developed cellular models to observe desmin behaviour in early stages of disease pathology, e.g., upon formation of cytoplasmic desmin aggregates, within an isogenic background. We cloned the wildtype and three mutant desmin cDNAs using a Tet-On Advanced® expression system in C2C12 cells. Mutations were selected based on positioning within desmin and capacity to form aggregates in transient experiments, as follows: DesS46Y (head domain; low aggregation), DesD399Y (central rod domain; high aggregation), and DesS460I (tail domain; moderate aggregation). Introduction of these proteins into a C2C12 background permitted us to compare between desmin variants as well as to determine the role of external stress on aggregation. Three different types of stress, likely encountered during muscle activity, were introduced to the cell models—thermal (heat shock), redox-associated (H2O2 and cadmium chloride), and mechanical (stretching) stresses—after which aggregation was measured. Cells containing variant DesD399Y were more sensitive to stress, leading to marked cytoplasmic perinuclear aggregations. We then evaluated the capacity of biochemical compounds to prevent this aggregation, applying dexamethasone (an inducer of heat shock proteins), fisetin or N-acetyl-L-cysteine (antioxidants) before stress induction. Interestingly, N-acetyl-L-cysteine pre-treatment prevented DesD399Y aggregation during most stress. N-acetyl-L-cysteine has recently been described as a promising antioxidant in myopathies linked to selenoprotein N or ryanodin receptor defects. Our findings indicate that this drug warrants further study in animal models to speed its potential development as a therapy for DesD399Y-linked desminopathies.

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Section: Discussionsupporting

confidence: 92%

N-Acetyl-L-Cysteine Prevents Stress-Induced Desmin Aggregation in Cellular Models of Desminopathy

et al. 2013

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“…Desmin aggregates were readily evident, diagnostic of a desmin-related myopathy (Figure 3C). 31, 32 Segregation analysis could not be performed as all affected family members had died or were unavailable for testing. Epitope-tagged DES R127P or wildtype desmin was introduced into myogenic C2C12 cells to assess pathogenicity.…”

Section: Resultsmentioning

confidence: 99%

Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy

Golbus

Puckelwartz

Dellefave‐Castillo

et al. 2014

Circ Cardiovasc Genet

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Background Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of more than 50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift towards comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy. Methods and Results Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused on 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1-14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and/or segregation analysis. Three of three previously identified primary mutations were detected by this analysis. In six subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and/or had additional pathological correlation to provide evidence for causality. For two subjects with previously known primary mutations, we identified additional variants that may act as modifiers of disease severity. In total, we identified the likely pathological mutation in 9 of 11 (82%) subjects. Conclusions These pilot data demonstrate that ~30-40× coverage whole genome sequencing combined with targeted analysis is feasible and sensitive to identify rare variants in cardiomyopathy-associated genes.

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“…The myopathic phenotype, however, is less severe than that of desmin-null mice, where absence of desmin results in more degenerated muscle fibres, severe perturbations of mitochondria localisation and extensive sarcomere disorganisation (Agbulut et al, 2001;Li et al, 1996;Li et al, 1997;Milner et al, 1996). This difference might be linked to the nature of synemin, which forms obligatory heteropolymers with desmin in mature skeletal muscle fibres (Chourbagi et al, 2011;Titeux et al, 2001). Indeed, localisation of synemin in muscle tissue depends on the presence of desmin (Carlsson et al, 2000;Titeux et al, 2001;Xue et al, 2004); thus, desmin-knockout mice would also lose synemin activity in muscle.…”

Section: Synemin Is Necessary For Sarcolemmal Membrane Integrity and mentioning

confidence: 99%

“…Synemin is unique in that it cannot homopolymerise to form filament networks, and therefore requires an appropriate copolymerisation partner, such as desmin, vimentin or keratin, depending on the cell type, to form filamentous structures (Bellin et al, 1999;Chourbagi et al, 2011;Hirako et al, 2003;Khanamiryan et al, 2008). Consequently, synemin filaments are unstable and delocalised in the cells of mice lacking desmin or vimentin (Carlsson et al, 2000;Izmiryan et al, 2006;Izmiryan et al, 2009;Jing et al, 2007;Xue et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Synemin acts as a regulator of signalling molecules in skeletal muscle hypertrophy

Li¹,

Parlakian²,

Coletti³

et al. 2014

Journal of Cell Science

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Synemin, a type IV intermediate filament (IF) protein, forms a bridge between IFs and cellular membranes. As an A-kinase-anchoring protein, it also provides temporal and spatial targeting of protein kinase A (PKA). However, little is known about its functional roles in either process. To better understand its functions in muscle tissue, we generated synemin-deficient (Synm 2/2 ) mice. Synm 2/2 mice displayed normal development and fertility but showed a mild degeneration and regeneration phenotype in myofibres and defects in sarcolemma membranes. Following mechanical overload, Synm 2/2 mice muscles showed a higher hypertrophic capacity with increased maximal force and fatigue resistance compared with control mice. At the molecular level, increased remodelling capacity was accompanied by decreased myostatin (also known as GDF8) and atrogin (also known as FBXO32) expression, and increased follistatin expression. Furthermore, the activity of muscle-mass control molecules (the PKA RIIa subunit, p70S6K and CREB1) was increased in mutant mice. Finally, analysis of muscle satellite cell behaviour suggested that the absence of synemin could affect the balance between self-renewal and differentiation of these cells. Taken together, our results show that synemin is necessary to maintain membrane integrity and regulates signalling molecules during muscle hypertrophy.

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Desmin mutations in the terminal consensus motif prevent synemin-desmin heteropolymer filament assembly

Cited by 26 publications

References 42 publications

N-Acetyl-L-Cysteine Prevents Stress-Induced Desmin Aggregation in Cellular Models of Desminopathy

N-Acetyl-L-Cysteine Prevents Stress-Induced Desmin Aggregation in Cellular Models of Desminopathy

Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy

Synemin acts as a regulator of signalling molecules in skeletal muscle hypertrophy

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