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Kay E. Davies - One of the best experts on this subject based on the ideXlab platform.
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Regenerative biomarkers for Duchenne muscular dystrophy
Medknow Publications, 2019Co-Authors: Simon Guiraud, Kay E. DaviesAbstract:Skeletal muscle has an extraordinary capacity to regenerate after injury and trauma. The muscle repair mechanism is a Complex process orchestrated by multiple steps. In neuromuscular disorders such as Duchenne muscular dystrophy (DMD), the pathological consequences of the lack of dystrophin and the loss of the Dystrophin-Associated Protein Complex are dramatic, with a progressive cascade of events, such as continual influx of inflammation, repeated cycles of degeneration and impaired regeneration. Thus, muscle regeneration is a hallmark of the disease and careful monitoring of regenerative processes with robust markers should provide useful information to the field. Since decades, several indices of regeneration such as centronucleation and fibre size have been commonly used. In the present review, we discuss the impaired regenerative process in DMD, the common and new indices of regeneration and their associated methodologies. We notably highlight the regenerative marker embryonic myosin as a robust indicator of muscle regeneration. We also describe new quantitative methodologies offering the possibility of using a panel of translational regenerative biomarkers to obtain a more complete view of the regeneration processes. Upregulation of utrophin, an autosomal and functional paralogue of dystrophin, is one of the most promising therapeutic strategies as it targets the primary cause of the disease and is applicable to all DMD patients regardless their genetic defects. As utrophin is a regeneration associated Protein increased in dystrophic muscle, we discuss the correlation of utrophin levels after drug treatment with regeneration markers. The recent advances in technologies and complementary markers of muscle regeneration described in this review, provide an unprecedented opportunity to develop more robust utrophin DMD based strategies for all DMD patients
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Syncoilin modulates peripherin filament networks and is necessary for large-calibre motor neurons.
Journal of Cell Science, 2010Co-Authors: William T. Clarke, Karl J. A. Mccullagh, Ben Edwards, Matthew Burgess, Matthew Kemp, Catherine Moorwood, Diane L. Sherman, Kay E. DaviesAbstract:Syncoilin is an atypical type III intermediate filament (IF) Protein, which is expressed in muscle and is associated with the Dystrophin-Associated Protein Complex. Here, we show that syncoilin is expressed in both the central and peripheral nervous systems. Isoform Sync1 is dominant in the brain, but isoform Sync2 is dominant in the spinal cord and sciatic nerve. Peripherin is a type III IF Protein that has been shown to colocalise and interact with syncoilin. Our analyses suggest that syncoilin might function to modulate formation of peripherin filament networks through binding to peripherin isoforms. Peripherin is associated with the disease amyotrophic lateral sclerosis (ALS), thus establishing a link between syncoilin and ALS. A neuronal analysis of the syncoilin-null mouse (Sync−/−) revealed a reduced ability in accelerating treadmill and rotarod tests. This phenotype might be attributable to the impaired function of extensor digitorum longus muscle and type IIb fibres caused by a shift from large- to small-calibre motor axons in the ventral root.
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Syncoilin accumulation in two patients with desmin-related myopathy
Neuromuscular disorders : NMD, 2003Co-Authors: Emily V. Howman, Nicky Sullivan, Ellen P Poon, Joanna E Britton, David Hilton-jones, Kay E. DaviesAbstract:Abstract We have recently shown that syncoilin interacts with desmin in skeletal muscle and has a role in attaching and organising desmin filaments to the Z-lines. We have analysed patients with desmin accumulation and have found that syncoilin is both upregulated at the sarcolemma and aggregates with desmin indicating the presence of two distinct Protein populations. Additional Dystrophin-Associated Protein Complex components also accumulate. The striking finding was that α-dystrobrevin-1 and neuronal nitric oxide synthase (nNOS) are almost completely lost from the membrane of these patients indicating that the myopathy may result from both the abnormal accumulation of Proteins and an increase in ischaemic injury due to the loss of nNOS. We speculate that the loss of α-dystrobrevin from the membrane, and subsequent loss of nNOS, is due to the α-dystrobrevin–syncoilin–desmin interaction.
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association of syncoilin and desmin linking intermediate filament Proteins to the dystrophin associated Protein Complex
Journal of Biological Chemistry, 2002Co-Authors: Ellen Poon, Emily V. Howman, Sarah E. Newey, Kay E. DaviesAbstract:Abstract We recently identified a novel Protein called syncoilin, a putative intermediate filament Protein that interacts with α-dystrobrevin, a member of the Dystrophin-Associated Protein Complex. Syncoilin is found at the neuromuscular junction, sarcolemma, and Z-lines and is thought to be important for muscle fiber integrity. Based on the similar Protein structure and cellular localization of syncoilin and desmin, we proposed that these Proteins interact in vivo. The data presented confirm an interaction between syncoilin and desmin and demonstrate their co-localization in skeletal muscle. Intriguingly, whereas these Proteins interact, COS-7 cell expression studies show that desmin and syncoilin do not assemble into heterofilaments. Furthermore, fractionation assay and immunofluorescence study of H2K myoblasts and myotubes suggest that, unlike typical intermediate filament Proteins, syncoilin does not participate in filament formation with any Protein. However, it is possible that syncoilin is involved in the anchoring of the desmin intermediate filament network at the sarcolemma and the neuromuscular junction. This interaction is likely to be important for maintaining muscle fiber integrity and may also link the Dystrophin-Associated Protein Complex to the cytoskeleton. The dysfunction or absence of syncoilin may result in the disruption of the intermediate filament network leading to muscle necrosis. Syncoilin is therefore an ideal candidate gene for muscular dystrophies and desmin-related myopathies.
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Role of beta-dystrobrevin in nonmuscle Dystrophin-Associated Protein Complex-like Complexes in kidney and liver.
Molecular and Cellular Biology, 2001Co-Authors: Nellie Y. Loh, Derek J Blake, Daniela Nebenius-oosthuizen, Andrew J.h. Smith, Kay E. DaviesAbstract:β-Dystrobrevin is a dystrophin-related and -associated Protein that is highly expressed in brain, kidney, and liver. Recent studies with the kidneys of the mdx3Cv mouse, which lacks all dystrophin isoforms, suggest that β-dystrobrevin, and not the dystrophin isoforms, may be the key component in the assembly of Complexes similar to the muscle Dystrophin-Associated Protein Complexes (DPC) in nonmuscle tissues. To understand the role of β-dystrobrevin in the function of nonmuscle tissues, we generated β-dystrobrevin-deficient (dtnb−/−) mice by gene targeting. dtnb−/− mice are healthy, fertile, and normal in appearance. No β-dystrobrevin was detected in these mice by Western blotting or immunocytochemistry. In addition, the levels of several β-dystrobrevin-interacting Proteins, namely Dp71 isoforms and the syntrophins, were greatly reduced from the basal membranes of kidney tubules and liver sinusoids and on Western blots of crude kidney and liver microsomes of β-dystrobrevin-deficient mice. However, no abnormality was detected in the ultrastructure of membranes of kidney and liver cells or in the renal function of these mice. β-Dystrobrevin may therefore be an anchor or scaffold for Dp71 and syntrophin isoforms, as well as other associating Proteins at the basal membranes of kidney and liver, but is not necessary for the normal function of these mice.
Israel Ramirezsanchez - One of the best experts on this subject based on the ideXlab platform.
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effects of epicatechin on frontal cortex dapc and dysbindin of the mdx mice
Neuroscience Letters, 2017Co-Authors: Francisco Javier Estradamena, Alonso Rodriguez, Patricia Mendozalorenzo, Teresa Nerigomez, Gabriel Manjarrezgutierrez, Andric C Perezortiz, Rosa Maria Ordonezrazo, Guillermo Ceballos, Francisco Villarreal, Israel RamirezsanchezAbstract:Abstract Introduction Multiple components of the Dystrophin-Associated Protein Complex (DAPC) are expressed in numerous tissues including the brain. Members of the DAPC and dysbindin are abnormally expressed in the brain of Duchenne Muscular Dystrophy (DMD) patients, which has been associated with cognitive impairments. However, little is known about the expression pattern of individual members of the DAPC in animal models of DMD and their relationship with dysbindin. Methods Ten mdx mice were randomly allocated into a control and intervention group [(−)-epicatechin (Epi) 1 mg/kg/day for four weeks] and results compared to a wild-type mice. After sacrifice, brain pre-frontal cortices were collected for Western blotting and immunoprecipitation assays, and sagittal sections processed for immunohistochemistry. Results Epi promotes a partial recovery of DAPC members [α1-Syntrophin, sarcoglycans (SG), dystrophin 71 (Dp71)], dysbindin, and utrophin Protein levels. Epi also appears to restore the association of DAPC between dysbindin, and utrophin with Dp71 and e-SG. Co-immunostaining evidence increased Protein levels of dysbindin, dystrophin, and e-SG and their colocalization. Conclusions Altogether, results suggest that Epi is capable of restoring pre-frontal cortex DAPC and dysbindin levels of mdx mice towards that of healthy brains. The functional implications of such studies warrant further investigation.
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el subcomplejo sarcoglicano sarcospan su importancia en el musculo estriado y tejido vascular
Investigación en Discapacidad, 2016Co-Authors: Ramon Mauricio Coralvazquez, Bladimir Roque Ramirez, Carlos Palmaflores, Israel Ramirezsanchez, Sergio De Los Santos, Patricia CantoAbstract:The sarcoglycans are members of a group of transmembrane Proteins closely related to a larger Complex of Proteins associated with dystrophin (DAPC, Dystrophin Associated Protein Complex). Initially, four sarcoglycan were described in the sarcolemma of skeletal muscle fibers (α-, β-, γand δ-SG). The SG subComplex, along with the Protein sarcospan and the subComplex dystroglycan (DG), is part of a scaffold that binds the extracellular matrix with the cytoskeleton. All these Proteins together protect the cell from mechanical damage during contraction the process. Additionally, there are evidences of their participation in signal transduction mechanisms. Mutations in these Proteins are the cause of limb girdle muscular dystrophy 2C-F (LGMD 2C-F). Other isoforms of SGs, eand ζ-, have not been associated with muscular dystrophy; although mutations in e-SG can cause diseases such as myoclonic dystonia. Deficiency or absence of β-, γand δ-SG has been as well associated with dilated cardiomyopathy. In this regard, various studies have revealed the presence of alternate forms of SG Complex in vascular smooth muscle and endothelium, and the relevance of these Proteins in vascular physiology. * Seccion de Estudios de Postgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, D.F., Mexico. ‡ Subdireccion de Ensenanza e Investigacion, CMN 20 de Noviembre, ISSSTE, Mexico, D.F., Mexico. § Division de Investigacion Biomedica, Subdireccion de Ensenanza e Investigacion, CMN 20 de Noviembre, ISSSTE, Mexico, D.F., Mexico. II Unidad de Investigacion en Obesidad, Facultad de Medicina, UNAM. Clinica de Obesidad, Instituto Nacional de Ciencias Medicas y Nutricion «Salvador Zubiran». Direccion para correspondencia: Ramon M. Coral-Vazquez Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Plan de San Luis y Diaz Miron s/n, Col. Casco de Santo Tomas, Del. Miguel Hidalgo. 11340, Mexico, D.F., Mexico. E-mail: rmcoralv@gmail.com rcoral@ipn.mx Recibido: 30 de junio de 2015. Aceptado: 7 de agosto de 2015. Este articulo puede ser consultado en version completa en: http://www.medigraphic.com/rid Palabras clave: Complejo sarcoglicano, musculo estriado, tejido vascular.
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el subcomplejo sarcoglicano sarcospan su importancia en el musculo estriado y tejido vascular the sarcospan sarcoglycan subComplex its importance in striated muscle and vascular tissue
2016Co-Authors: Ramon Mauricio Coralvazquez, Bladimir Roque Ramirez, Carlos Palmaflores, Israel Ramirezsanchez, Patricia CantoAbstract:The sarcoglycans are members of a group of transmembrane Proteins closely related to a larger Complex of Proteins associated with dystrophin (DAPC, Dystrophin Associated Protein Complex). Initially, four sarcoglycan were described in the sarcolemma of skeletal muscle fibers (α-, β-, γ- and δ-SG). The SG subComplex, along with the Protein sarcospan and the subComplex dystroglycan (DG), is part of a scaffold that binds the extracellular matrix with the cytoskeleton. All these Proteins together protect the cell from mechanical damage during contraction the process. Additionally, there are evidences of their participation in signal transduction mechanisms. Mutations in these Proteins are the cause of limb girdle muscular dystrophy 2C -F (LGMD 2C-F). Other isoforms of SGs, e- and ζ-, have not been associated with muscular dystrophy; although mutations in e-SG can cause diseases such as myoclonic dystonia. Deficiency or absence of β-, γ- and δ-SG has been as well associated with dilated cardiomyopathy. In this regard, various studies have revealed the presence of alternate forms of SG Complex in vascular smooth muscle and endothelium, and the relevance of these Proteins in vascular physiology. * Seccion de Estudios de Postgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico, D.F., Mexico. ‡ Subdireccion de Ensenanza e Investigacion, CMN 20 de Noviembre, ISSSTE, Mexico, D.F., Mexico. § Di vision de Investigacion Biomedica, Subdireccion de Ensenanza e Investigacion, CMN 20 de Noviembre, ISSSTE, Mexico, D.F., Mexico. II Unidad de Investigacion en Obesidad, F acultad de Medicina, UNAM. Clinica de Obesidad, Instituto Nacional de Ciencias Medicas y Nutricion «Salvador Zubiran».
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perturbations in skeletal muscle sarcomere structure in patients with heart failure and type 2 diabetes restorative effects of epicatechin rich cocoa
Clinical Science, 2013Co-Authors: Pam R Taub, Ramon Mauricio Coralvazquez, Israel Ramirezsanchez, Theodore P Ciaraldi, Silvia Gonzalezbasurto, Guy A Perkins, Michael C Hogan, Alan S Maisel, Robert R HenryAbstract:HF (heart failure) and T2D (Type 2 diabetes) associate with detrimental alterations in SkM (skeletal muscle) structure/function. We have demonstrated recently that (-)-ERC (epicatechin-rich cocoa) improves SkM mitochondrial structure [Taub, Ramirez-Sanchez, Ciaraldi, Perkins, Murphy, Naviaux, Hogan, Ceballos, Maisel, Henry et al. (2012) Clin. Trans. Sci. 5, 43-47]. We hypothesized that an improved mitochondrial structure may facilitate the reversal of detrimental alterations in sarcomeric microstructure. In a pilot study, five patients with HF and T2D consumed ERC for 3 months; treadmill testing [VO2max (maximum oxygen consumption)] and SkM biopsies were performed. Western blot analysis, immunohistochemistry and electron microscopy were used. We report severe perturbations in components of the DAPC (Dystrophin-Associated Protein Complex) as well as sarcomeric microstructure at baseline. ERC induced recovery/enhancement of DAPC Protein levels, sarcomeric microstructure and, in a co-ordinated fashion, alterations in markers of SkM growth/differentiation consistent with myofibre regeneration. VO2max increased (~24%) but did not reach statistical significance. These initial results warrant further rigorous investigation, since the use of ERC (or pure epicatechin) may represent a safe and novel means of improving muscle function.
Louis M Kunkel - One of the best experts on this subject based on the ideXlab platform.
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gene expression comparison of biopsies from duchenne muscular dystrophy dmd and normal skeletal muscle
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Judith N Haslett, Despina Sanoudou, Richard R Bennett, Steven A Greenberg, Isaac S Kohane, Alan H Beggs, Louis M KunkelAbstract:The primary cause of Duchenne muscular dystrophy (DMD) is a mutation in the dystrophin gene leading to the absence of the corresponding RNA transcript and Protein. Absence of dystrophin leads to disruption of the Dystrophin-Associated Protein Complex and substantial changes in skeletal muscle pathology. Although the histological pathology of dystrophic tissue has been well documented, the underlying molecular pathways remain poorly understood. To examine the pathogenic pathways and identify new or modifying factors involved in muscular dystrophy, expression microarrays were used to compare individual gene expression profiles of skeletal muscle biopsies from 12 DMD patients and 12 unaffected control patients. Two separate statistical analysis methods were used to interpret the resulting data: t test analysis to determine the statistical significance of differential expression and geometric fold change analysis to determine the extent of differential expression. These analyses identified 105 genes that differ significantly in expression level between unaffected and DMD muscle. Many of the differentially expressed genes reflect changes in histological pathology. For instance, immune response signals and extracellular matrix genes are overexpressed in DMD muscle, an indication of the infiltration of inflammatory cells and connective tissue. Significantly more genes are overexpressed than are underexpressed in dystrophic muscle, with dystrophin underexpressed, whereas other genes encoding muscle structure and regeneration processes are overexpressed, reflecting the regenerative nature of the disease.
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Desmuslin, an intermediate filament Protein that interacts with α-dystrobrevin and desmin
Proceedings of the National Academy of Sciences, 2001Co-Authors: Yuji Mizuno, Michihiro Imamura, Eijiro Ozawa, Terri G. Thompson, Jeffrey Robert Guyon, Hart G.w. Lidov, Melissa Brosius, Simon C. Watkins, Louis M KunkelAbstract:Abstract Dystrobrevin is a component of the Dystrophin-Associated Protein Complex and has been shown to interact directly with dystrophin, α1-syntrophin, and the sarcoglycan Complex. The precise role of α-dystrobrevin in skeletal muscle has not yet been determined. To study α-dystrobrevin's function in skeletal muscle, we used the yeast two-hybrid approach to look for interacting Proteins. Three overlapping clones were identified that encoded an intermediate filament Protein we subsequently named desmuslin (DMN). Sequence analysis revealed that DMN has a short N-terminal domain, a conserved rod domain, and a long C-terminal domain, all common features of type 6 intermediate filament Proteins. A positive interaction between DMN and α-dystrobrevin was confirmed with an in vitro coimmunoprecipitation assay. By Northern blot analysis, we find that DMN is expressed mainly in heart and skeletal muscle, although there is some expression in brain. Western blotting detected a 160-kDa Protein in heart and skeletal muscle. Immunofluorescent microscopy localizes DMN in a stripe-like pattern in longitudinal sections and in a mosaic pattern in cross sections of skeletal muscle. Electron microscopic analysis shows DMN colocalized with desmin at the Z-lines. Subsequent coimmunoprecipitation experiments confirmed an interaction with desmin. Our findings suggest that DMN may serve as a direct linkage between the extracellular matrix and the Z-discs (through plectin) and may play an important role in maintaining muscle cell integrity.
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Analysis of human sarcospan as a candidate gene for CFEOM1
BMC Genetics, 2001Co-Authors: Kristine F O'brien, Elizabeth C Engle, Louis M KunkelAbstract:Background Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is an autosomal dominant eye movement disorder linked to the pericentromere of chromosome 12 (12p11.2 - q12). Sarcospan is a member of the dystrophin associated Protein Complex in skeletal and extraocular muscle and maps to human chromosome 12p11.2. Mutations in the genes encoding each of the other components of the skeletal muscle sarcospan-sarcoglycan Complex (α - δ sarcoglycan) have been shown to cause limb girdle muscular dystrophy (LGMD2C-F). To determine whether mutations in the sarcospan gene are responsible for CFEOM1 we: (1) attempted to map sarcospan to the CFEOM1 critical region; (2) developed a genomic primer set to directly sequence the sarcospan gene in CFEOM1 patients; and (3) generated an anti-sarcospan antibody to examine extraocular muscle biopsies from CFEOM1 patients. Results When tested by polymerase chain reaction, sarcospan sequence was not detected on yeast or bacterial artificial chromosomes from the CFEOM1 critical region. Sequencing of the sarcospan gene in CFEOM1 patients from 6 families revealed no mutations. Immunohistochemical studies of CFEOM1 extraocular muscles showed normal levels of sarcospan at the membrane. Finally, sarcospan was electronically mapped to bacterial artificial chromosomes that are considered to be outside of the CFEOM1 critical region. Conclusions In this report we evaluate sarcospan as a candidate gene for CFEOM1. We have found that it is highly unlikely that sarcospan is involved in the pathogenesis of this disease. As of yet no sarcospan gene mutations have been found to cause muscular abnormalities.
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Analysis of human sarcospan as a candidate gene for CFEOM1
2001Co-Authors: Kristine F. O&apos, Louis M Kunkel, Elizabeth C EngleAbstract:(c) 2001 O'Brien et al, licensee BioMed Central Ltd. Background: Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is an autosomal dominant eye movement disorder linked to the pericentromere of chromosome 12 (12p11.2-q12). Sarcospan is a member of the dystrophin associated Protein Complex in skeletal and extraocular muscle and maps to human chromosome 12p11.2. Mutations in the genes encoding each of the other components of the skeletal muscle sarcospan-sarcoglycan Complex (α- δ sarcoglycan) have been shown to cause limb girdle muscular dystrophy (LGMD2C-F). To determine whether mutations in the sarcospan gene are responsible for CFEOM1 we: (1) attempted to map sarcospan to the CFEOM1 critical region; (2) developed a genomic primer set to directly sequence the sarcospan gene in CFEOM1 patients; and (3) generated an anti-sarcospan antibody to examine extraocular muscle biopsies from CFEOM1 patients. Results: When tested by polymerase chain reaction, sarcospan sequence was not detected on yeast or bacterial artificial chromosomes from the CFEOM1 critical region. Sequencing of the sarcospan gene in CFEOM1 patients from 6 families revealed no mutations. Immunohistochemica
John D. Scott - One of the best experts on this subject based on the ideXlab platform.
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α dystrobrevin 1 recruits α catulin to the α 1d adrenergic receptor dystrophin associated Protein Complex signalosome
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: John S. Lyssand, Jennifer L. Whiting, Kyung Soon Lee, Ryan Kastl, Jennifer L. Wacker, Michael R. Bruchas, Mayumi Miyatake, Lorene K. Langeberg, Charles Chavkin, John D. ScottAbstract:α1D-Adrenergic receptors (ARs) are key regulators of cardiovascular system function that increase blood pressure and promote vascular remodeling. Unfortunately, little information exists about the signaling pathways used by this important G Protein-coupled receptor (GPCR). We recently discovered that α1D-ARs form a “signalosome” with multiple members of the Dystrophin-Associated Protein Complex (DAPC) to become functionally expressed at the plasma membrane and bind ligands. However, the molecular mechanism by which the DAPC imparts functionality to the α1D-AR signalosome remains a mystery. To test the hypothesis that previously unidentified molecules are recruited to the α1D-AR signalosome, we performed an extensive proteomic analysis on each member of the DAPC. Bioinformatic analysis of our proteomic data sets detected a common interacting Protein of relatively unknown function, α-catulin. Coimmunoprecipitation and blot overlay assays indicate that α-catulin is directly recruited to the α1D-AR signalosome by the C-terminal domain of α-dystrobrevin-1 and not the closely related splice variant α-dystrobrevin-2. Proteomic and biochemical analysis revealed that α-catulin supersensitizes α1D-AR functional responses by recruiting effector molecules to the signalosome. Taken together, our study implicates α-catulin as a unique regulator of GPCR signaling and represents a unique expansion of the intricate and continually evolving array of GPCR signaling networks.
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α dystrobrevin 1 recruits α catulin to the α1d adrenergic receptor dystrophin associated Protein Complex signalosome
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: John S. Lyssand, Jennifer L. Whiting, Kyung Soon Lee, Ryan Kastl, Jennifer L. Wacker, Michael R. Bruchas, Mayumi Miyatake, Lorene K. Langeberg, Charles Chavkin, John D. ScottAbstract:α1D-Adrenergic receptors (ARs) are key regulators of cardiovascular system function that increase blood pressure and promote vascular remodeling. Unfortunately, little information exists about the signaling pathways used by this important G Protein-coupled receptor (GPCR). We recently discovered that α1D-ARs form a “signalosome” with multiple members of the Dystrophin-Associated Protein Complex (DAPC) to become functionally expressed at the plasma membrane and bind ligands. However, the molecular mechanism by which the DAPC imparts functionality to the α1D-AR signalosome remains a mystery. To test the hypothesis that previously unidentified molecules are recruited to the α1D-AR signalosome, we performed an extensive proteomic analysis on each member of the DAPC. Bioinformatic analysis of our proteomic data sets detected a common interacting Protein of relatively unknown function, α-catulin. Coimmunoprecipitation and blot overlay assays indicate that α-catulin is directly recruited to the α1D-AR signalosome by the C-terminal domain of α-dystrobrevin-1 and not the closely related splice variant α-dystrobrevin-2. Proteomic and biochemical analysis revealed that α-catulin supersensitizes α1D-AR functional responses by recruiting effector molecules to the signalosome. Taken together, our study implicates α-catulin as a unique regulator of GPCR signaling and represents a unique expansion of the intricate and continually evolving array of GPCR signaling networks.
Derek J Blake - One of the best experts on this subject based on the ideXlab platform.
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myoclonus dystonia and muscular dystrophy ɛ sarcoglycan is part of the dystrophin associated Protein Complex in brain
Movement Disorders, 2016Co-Authors: Adrian James Waite, Francesca A Carlisle, Yiumo Michael Chan, Derek J BlakeAbstract:BACKGROUND: Myoclonus-dystonia is a neurogenic movement disorder caused by mutations in the gene encoding ɛ-sarcoglycan. By contrast, mutations in the α-, β-, γ-, and δ-sarcoglycan genes cause limb girdle muscular dystrophies. The sarcoglycans are part of the Dystrophin-Associated Protein Complex in muscle that is disrupted in several types of muscular dystrophy. Intriguingly, patients with myoclonus-dystonia have no muscle pathology; conversely, limb-girdle muscular dystrophy patients have not been reported to have dystonia-associated features. To gain further insight into the molecular mechanisms underlying these differences, we searched for evidence of a sarcoglycan Complex in the brain. METHODS: Immunoaffinity chromatography and mass spectrometry were used to purify ubiquitous and brain-specific ɛ-sarcoglycan directly from tissue. Cell models were used to determine the effect of mutations on the trafficking and assembly of the brain sarcoglycan Complex. RESULTS: Ubiquitous and brain-specific ɛ-sarcoglycan isoforms copurify with β-, δ-, and ζ-sarcoglycan, β-dystroglycan, and dystrophin Dp71 from brain. Incorporation of a muscular dystrophy-associated β-sarcoglycan mutant into the brain sarcoglycan Complex impairs the formation of the βδ-sarcoglycan core but fails to abrogate the association and membrane trafficking of ɛ- and ζ-sarcoglycan. CONCLUSIONS: ɛ-Sarcoglycan is part of the Dystrophin-Associated Protein Complex in brain. Partial preservation of ɛ- and ζ-sarcoglycan in brain may explain the absence of myoclonus dystonia-like features in muscular dystrophy patients. © 2016 International Parkinson and Movement Disorder Society.
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Different Dystrophin-like Complexes Are Expressed in Neurons and Glia
2013Co-Authors: Derek J Blake, Richard Hawkes, Matthew A. Benson, Phillip W. BeesleyAbstract:Abstract. Duchenne muscular dystrophy is a fatal muscle disease that is often associated with cognitive impairment. Accordingly, dystrophin is found at the muscle sarcolemma and at postsynaptic sites in neurons. In muscle, dystrophin forms part of a membrane-spanning Complex, the Dystrophin-Associated Protein Complex (DPC). Whereas the composition of the DPC in muscle is well documented, the existence of a similar Complex in brain remains largely unknown. To determine the composition of DPC-like Complexes in brain, we have examined the molecular associations and distribution of the dystrobrevins, a widely expressed family of Dystrophin-Associated Proteins, some of which are components of the muscle DPC. �-Dystrobrevin is found in neurons and is highly enriched in postsynaptic densitie
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hermansky pudlak syndrome type 7 hps 7 results from mutant dysbindin a member of the biogenesis of lysosome related organelles Complex 1 bloc 1
Nature Genetics, 2003Co-Authors: Qing Zhang, Derek J Blake, Caroline L. Tinsley, Naoki Oiso, Edward K Novak, Rashi Gautam, Edward P Obrien, Richard A Spritz, Neal G Copeland, Nancy A JenkinsAbstract:Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules. In mice, at least 16 loci are associated with HPS, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no dysbindin Protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed Protein that binds to alpha- and beta-dystrobrevins, components of the Dystrophin-Associated Protein Complex (DPC) in both muscle and nonmuscle cells. We also show that dysbindin is a component of the biogenesis of lysosome-related organelles Complex 1 (BLOC-1; refs. 9-11), which regulates trafficking to lysosome-related organelles and includes the Proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1.
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abnormal dysbindin expression in cerebellar mossy fiber synapses in the mdx mouse model of duchenne muscular dystrophy
The Journal of Neuroscience, 2003Co-Authors: Roy V Sillitoe, Derek J Blake, Matthew A. Benson, Richard HawkesAbstract:The Dystrophin-Associated Protein Complex (DPC), comprising sarcoglycans, dystroglycans, dystrobrevins, and syntrophins, is a component of synapses both in muscle and brain. Dysbindin is a novel component of the DPC, which binds to beta-dystrobrevin and may serve as an adaptor Protein that links the DPC to an intracellular signaling cascade. Disruption of the DPC results in muscular dystrophy, and mutations in the human ortholog of dysbindin have been implicated in the pathogenesis of schizophrenia. In both cases, patients also present with neurological symptoms reminiscent of cerebellar problems. In the mouse cerebellum, dysbindin immunoreactivity is expressed at high levels in a subset of mossy fiber synaptic glomeruli in the granular layer. Lower levels of dysbindin immunoreactivity are also detected in Purkinje cell dendrites. In the cerebellar vermis, dysbindin-immunoreactive glomeruli are restricted to an array of parasagittal stripes that bears a consistent relationship to Purkinje cell parasagittal band boundaries as defined by the expression of the respiratory isoenzyme zebrin II/aldolase c. In a mouse model of Duchenne muscular dystrophy, the mdx mutant, in which dystrophin is not expressed, there is a dramatic increase in the number of dysbindin-immunoreactive glomeruli in the posterior cerebellar vermis. Moreover, the topography of the terminal fields is disrupted, replacing the stripes by a homogeneous distribution. Abnormal synaptic organization in the cerebellum may contribute to the neurological problems associated with muscular dystrophy and schizophrenia.
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Role of beta-dystrobrevin in nonmuscle Dystrophin-Associated Protein Complex-like Complexes in kidney and liver.
Molecular and Cellular Biology, 2001Co-Authors: Nellie Y. Loh, Derek J Blake, Daniela Nebenius-oosthuizen, Andrew J.h. Smith, Kay E. DaviesAbstract:β-Dystrobrevin is a dystrophin-related and -associated Protein that is highly expressed in brain, kidney, and liver. Recent studies with the kidneys of the mdx3Cv mouse, which lacks all dystrophin isoforms, suggest that β-dystrobrevin, and not the dystrophin isoforms, may be the key component in the assembly of Complexes similar to the muscle Dystrophin-Associated Protein Complexes (DPC) in nonmuscle tissues. To understand the role of β-dystrobrevin in the function of nonmuscle tissues, we generated β-dystrobrevin-deficient (dtnb−/−) mice by gene targeting. dtnb−/− mice are healthy, fertile, and normal in appearance. No β-dystrobrevin was detected in these mice by Western blotting or immunocytochemistry. In addition, the levels of several β-dystrobrevin-interacting Proteins, namely Dp71 isoforms and the syntrophins, were greatly reduced from the basal membranes of kidney tubules and liver sinusoids and on Western blots of crude kidney and liver microsomes of β-dystrobrevin-deficient mice. However, no abnormality was detected in the ultrastructure of membranes of kidney and liver cells or in the renal function of these mice. β-Dystrobrevin may therefore be an anchor or scaffold for Dp71 and syntrophin isoforms, as well as other associating Proteins at the basal membranes of kidney and liver, but is not necessary for the normal function of these mice.
