Disorganization of the Desmin Cytoskeleton and Mitochondrial Dysfunction in Plectin-Related Epidermolysis Bullosa Simplex with Muscular Dystrophy

Schröder, Rolf; Kunz, Wolfram S.; Rouan, Fatima; Pfendner, Ellen G; Tolksdorf, Karen; Kappes-Horn, Karin; Altenschmidt-Mehring, Manuela; Knoblich, Rupert; Ven, Peter F.M. van der; Reimann, Jens; Fürst, Dieter O.; Blümcke, Ingmar; Vielhaber, Stefan; Zillikens, Detlef; Eming, Sabine A.; Klockgether, Thomas; Uitto, Jouni; Wiche, Gerhard; Rolfs, Arndt

doi:10.1093/jnen/61.6.520

Cited by 97 publications

(118 citation statements)

References 54 publications

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“…23 A homozygous insertion close to the IF-binding domain of plectin has been linked to epidermolysis bullosa simplex-muscular dystrophy in at least one patient who presented with marked desmin accumulations in muscle tissue and severe cerebral atrophy. 15 Combined with other case reports of brain atrophy associated with epidermolysis bullosa simplex, 24,25 this suggests that perturbations of the plectin/IF interactions due to plectin mutations or IF mutations can lead to neurological pathology.…”

Section: Implications For If Disorganization In Axdmentioning

confidence: 63%

“…First, plectin functions as a versatile cytoskeletal linker protein. 10 Second, plectin deficiency in humans results in a pathological condition called epidermolysis bullosa simplex with muscular dystrophy, 15 which is characterized by the disorganization of the desmin cytoskeleton. Third, plectin is abundant in reactive astrocytes of the CNS.…”

Section: Discussionmentioning

confidence: 99%

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Plectin Regulates the Organization of Glial Fibrillary Acidic Protein in Alexander Disease

Tian

Gregor

Wiche

et al. 2006

The American Journal of Pathology

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Alexander disease (AxD) is a rare but fatal neurological disorder caused by mutations in the astrocytespecific intermediate filament protein glial fibrillary acidic protein (GFAP). Histologically, AxD is characterized by cytoplasmic inclusion bodies called Rosenthal fibers (RFs), which contain GFAP, small heat shock proteins, and other undefined components. Here, we describe the expression of the cytoskeletal linker protein plectin in the AxD brain. RFs displayed positive immunostaining for plectin and GFAP, both of which were increased in the AxD brain. Co-localization, co-immunoprecipitation, and in vitro overlay analyses demonstrated direct interaction of plectin and GFAP. GFAP with the most common AxD mutation, R239C (RC GFAP), mainly formed abnormal aggregates in human primary astrocytes and murine plectin-deficient fibroblasts. Transient transfection of full-length plectin cDNA converted these aggregates to thin filaments, which exhibited diffuse cytoplasmic distribution. Compared to wild-type GFAP expression, RC GFAP expression lowered plectin levels in astrocytoma-derived stable transfectants and plectin-positive fibroblasts. A much higher proportion of total GFAP was found in the Triton X-insoluble fraction of plectin-deficient fibroblasts than in wild-type fibroblasts. Taken together, our results suggest that insufficient amounts of plectin, due to RC GFAP expression, promote GFAP aggregation and RF formation in AxD.

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Section: Implications For If Disorganization In Axdmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Plectin Regulates the Organization of Glial Fibrillary Acidic Protein in Alexander Disease

Tian

Gregor

Wiche

et al. 2006

The American Journal of Pathology

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“…This suggests that different types of IFs control mitochondrial distribution in the various striated muscles: desmin-based filaments in cardiomyocytes and slow-twitch myofibers, and keratin-based filaments in fast-twitch muscle. Mutations in intermediate filaments and plectin, which can associate with both intermediate filaments and mitochondria (Reipert et al, 1999), have been linked to mitochondrial defects in several murine and human diseases of muscle Schroder et al, 2002;Schroder et al, 2003). Mutations in other types of IFs are also associated with changes in mitochondrial location or function in a variety of cell types (Toivola et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Absence of keratin 19 in mice causes skeletal myopathy with mitochondrial and sarcolemmal reorganization

Stone

O’Neill

Lovering

et al. 2007

Journal of Cell Science

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Intermediate filaments, composed of desmin and of keratins, play important roles in linking contractile elements to each other and to the sarcolemma in striated muscle. We examined the contractile properties and morphology of fast-twitch skeletal muscle from mice lacking keratin 19. Tibialis anterior muscles of keratin-19-null mice showed a small but significant decrease in mean fiber diameter and in the specific force of tetanic contraction, as well as increased plasma creatine kinase levels. Costameres at the sarcolemma of keratin-19-null muscle, visualized with antibodies against spectrin or dystrophin, were disrupted and the sarcolemma was separated from adjacent myofibrils by a large gap in which mitochondria accumulated. The costameric dystrophin-dystroglycan complex, which co-purified with γ-actin, keratin 8 and keratin 19 from striated muscles of wild-type mice, co-purified with γ-actin but not keratin 8 in the mutant. Our results suggest that keratin 19 in fast-twitch skeletal muscle helps organize costameres and links them to the contractile apparatus, and that the absence of keratin 19 disrupts these structures, resulting in loss of contractile force, altered distribution of mitochondria and mild myopathy. This is the first demonstration of a mammalian phenotype associated with a genetic perturbation of keratin 19.

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“…28 In patients with PLEC1 (Plectin) and LDB3 (Zasp) mutations, nuclear rods have also been described. 29,30 To our knowledge, there are no reports describing actin aggregation in the context of diseases of the skeletal muscle otherwise.…”

Section: Molecular Analysis Of Myonuclear Actin Aggregation Inmentioning

confidence: 99%

Nuclear actin aggregation is a hallmark of anti-synthetase syndrome–induced dysimmune myopathy

et al. 2015

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Objective: To analyze antisynthetase syndrome-associated myositis by modern myopathologic methods and to define its place in the spectrum of idiopathic inflammatory myopathies (IIMs). Methods: Skeletal muscle biopsies from antisynthetase syndrome-associated myositis and other IIMs from different institutions worldwide were analyzed by histopathology, quantitative PCR, and electron microscopy. Results: Myonuclear actin filament inclusions were identified as a unique morphologic hallmark of antisynthetase syndrome-associated myositis. Nuclear actin inclusions were never found in dermatomyositis, polymyositis, sporadic inclusion body myositis, autoimmune necrotizing myopathy associated with signal recognition particle or 3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies, or nonspecific myositis associated with other systemic diseases, harboring myositis-associated autoantibodies, and presenting myofiber necrosis. We show that molecules involved in actin filament formation and actin shuttling mechanisms are altered in antisynthetase syndrome, and may thus be involved in pathologic myonuclear actin aggregation. In addition, we have identified a typical topographic distribution of necrotic myofibers predominantly located at the periphery of muscle fascicles accompanied by inflammation and destruction of the perimysial connective tissue. Conclusion: Antisynthetase syndrome-associated myositis is characterized by distinctive myonuclear actin filament inclusions, including rod formations and a typical necrotizing perimysial myositis. This supports the hypothesis that antisynthetase syndrome-associated myositis is unique and should not be grouped among dermatomyositis, polymyositis, sporadic inclusion body myositis, necrotizing autoimmune myositis, or nonspecific myositis. Classification of evidence: This study provides Class II evidence that for patients with IIMs, the presence of myonuclear actin filament inclusions accurately identifies patients with antisynthetase syndrome-associated myositis (sensitivity 81%, specificity 100%). Methods: Skeletal muscle biopsies from antisynthetase syndrome-associated myositis and otherIIMs from different institutions worldwide were analyzed by histopathology, quantitative PCR, and electron microscopy.Results: Myonuclear actin filament inclusions were identified as a unique morphologic hallmark of antisynthetase syndrome-associated myositis. Nuclear actin inclusions were never found in dermatomyositis, polymyositis, sporadic inclusion body myositis, autoimmune necrotizing myopathy associated with signal recognition particle or 3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies, or nonspecific myositis associated with other systemic diseases, harboring myositis-associated autoantibodies, and presenting myofiber necrosis. We show that molecules involved in actin filament formation and actin shuttling mechanisms are altered in antisynthetase syndrome, and may thus be involved in pathologic myonuclear actin aggregation. In addition, we have identified a ...

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Disorganization of the Desmin Cytoskeleton and Mitochondrial Dysfunction in Plectin-Related Epidermolysis Bullosa Simplex with Muscular Dystrophy

Cited by 97 publications

References 54 publications

Plectin Regulates the Organization of Glial Fibrillary Acidic Protein in Alexander Disease

Plectin Regulates the Organization of Glial Fibrillary Acidic Protein in Alexander Disease

Absence of keratin 19 in mice causes skeletal myopathy with mitochondrial and sarcolemmal reorganization

Nuclear actin aggregation is a hallmark of anti-synthetase syndrome–induced dysimmune myopathy

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