Role for α-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies

Grady, R. Mark; Grange, Robert W.; Lau, Kim S.; Maimone, Margaret M.; Nichol, Mia C.; Stull, James T.; Sanes, Joshua R.

doi:10.1038/12034

Cited by 284 publications

(179 citation statements)

References 48 publications

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“…The role of the dystrobrevins in signaling is not fully understood; however, targeted disruption of the ␣-dystrobrevin gene in mice results in muscle pathology without the membrane fragility characteristic of dystrophin-deficient muscular dystrophy (8). These findings suggest that ␣-dystrobrevin is important for muscle function but in a non-structural way.…”

mentioning

confidence: 72%

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

Albrecht

Froehner

2004

Journal of Biological Chemistry

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Mice rendered null for ␣-dystrobrevin, a component of the dystrophin complex, have muscular dystrophy, despite the fact that the sarcolemma remains relatively intact (Grady, R. M., Grange, R. W., Lau, K. S., Maimone, M. M., Nichol, M. C., Stull, J. T., and Sanes, J. R. (1999) Nat. Cell Biol. 1, 215-220) Thus, ␣-dystrobrevin may serve a signaling function that is important for the maintenance of muscle integrity. We have identified a new dystrobrevin-associated protein, DAMAGE, that may play a signaling role in brain, muscle, and peripheral nerve. In humans, DAMAGE is encoded by an intronless gene located at chromosome Xq13.1, a locus that contains genes involved in mental retardation. DAM-AGE associates directly with ␣-dystrobrevin, as shown by yeast two-hybrid, and co-immunoprecipitates with the dystrobrevin-syntrophin complex from brain. This co-immunoprecipitation is dependent on the presence of ␣-dystrobrevin but not ␤-dystrobrevin. The DAMAGE protein contains a potential nuclear localization signal, 30 12-amino acid repeats, and two MAGE homology domains. The domain structure of DAMAGE is similar to that of NRAGE, a MAGE protein that mediates p75 neurotrophin receptor signaling and neuronal apoptosis (Salehi, A. H., Roux, P. P., Kubu, C. J., Zeindler, C., Bhakar, A., Tannis, L. L., Verdi, J. M., and Barker, P. A. (2000) Neuron 27, 279 -288). DAMAGE is highly expressed in brain and is present in the cell bodies and dendrites of hippocampal and Purkinje neurons. In skeletal muscle, DAMAGE is at the postsynaptic membrane and is associated with a subset of myonuclei. DAMAGE is also expressed in peripheral nerve, where it localizes along with other members of the dystrophin complex to the perineurium and myelin. These results expand the role of dystrobrevin and the dystrophin complex in membrane signaling and disease.The dystrophin glycoprotein complex links the actin cytoskeleton to the extracellular matrix in skeletal muscle. In addition, recent studies (1-7) have shown that the dystrophin complex is critical for the localization of a variety of signaling molecules to the skeletal muscle sarcolemma. Thus, the dystrophin complex functions as both a structural link to the extracellular matrix and as a scaffold that concentrates and stabilizes functionally inter-related signaling proteins at the muscle cell membrane.Part of the signaling function of the dystrophin complex may be mediated by the dystrobrevins. The role of the dystrobrevins in signaling is not fully understood; however, targeted disruption of the ␣-dystrobrevin gene in mice results in muscle pathology without the membrane fragility characteristic of dystrophin-deficient muscular dystrophy (8). These findings suggest that ␣-dystrobrevin is important for muscle function but in a non-structural way. Dystrobrevin has no enzymatic activity of its own; therefore, the involvement of dystrobrevin in signaling pathways is dependent on its interaction with other proteins.The dystrobrevins are transcribed from two separate genes, designated ␣ and ␤, that shar...

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mentioning

confidence: 72%

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

Albrecht

Froehner

2004

Journal of Biological Chemistry

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Section: Duchenne Muscular Dystrophy (Dmd)mentioning

confidence: 99%

“…Recent experimental evidence has shown that ␣-dystrobrevin, a component of the DPC, may be involved in intracellular signaling (9). ␣-Dystrobrevin-deficient mice develop mild muscular dystrophy without disturbing the assembly of the DPC at the sarcolemma and altering the structural integrity of the muscle fiber (9).…”

Section: Duchenne Muscular Dystrophy (Dmd)mentioning

confidence: 99%

“…␣-Dystrobrevin-deficient mice develop mild muscular dystrophy without disturbing the assembly of the DPC at the sarcolemma and altering the structural integrity of the muscle fiber (9). These mice have reduced levels of intracellular cGMP and have less neuronal nitric-oxide synthase (nNOS) at the sarcolemma (9). The role of nNOS in the pathology of muscular dystrophy is unclear since similar alterations in nNOS have been described in ␣-syntrophin-deficient mice; however, these mice do not develop muscular dystrophy (10).…”

Section: Duchenne Muscular Dystrophy (Dmd)mentioning

confidence: 99%

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Dysbindin, a Novel Coiled-coil-containing Protein That Interacts with the Dystrobrevins in Muscle and Brain

Benson

Newey

Martin‐Rendon

et al. 2001

Journal of Biological Chemistry

278

262

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The dystrophin-associated protein complex (DPC) is required for the maintenance of muscle integrity during the mechanical stresses of contraction and relaxation. In addition to providing a membrane scaffold, members of the DPC such as the ␣-dystrobrevin protein family are thought to play an important role in intracellular signal transduction. To gain additional insights into the function of the DPC, we performed a yeast two-hybrid screen for dystrobrevin-interacting proteins. Here we describe the identification of a dysbindin, a novel dystrobrevinbinding protein. Dysbindin is an evolutionary conserved 40-kDa coiled-coil-containing protein that binds to ␣-and ␤-dystrobrevin in muscle and brain. Dystrophin and ␣-dystrobrevin are co-immunoprecipitated with dysbindin, indicating that dysbindin is DPC-associated in muscle. Dysbindin co-localizes with ␣-dystrobrevin at the sarcolemma and is up-regulated in dystrophin-deficient muscle. In the brain, dysbindin is found primarily in axon bundles and especially in certain axon terminals, notably mossy fiber synaptic terminals in the cerebellum and hippocampus. These findings have implications for the molecular pathology of Duchenne muscular dystrophy and may provide an alternative route for anchoring dystrobrevin and the DPC to the muscle membrane.

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“…Loss of dystroglycan in chimeric mice, for example, results in aberrant synapses in addition to muscular dystrophy (28). Likewise, ␣-dystrobrevin is important for the maturation and maintenance of the neuromuscular synapse and loss of ␣-dystrobrevin also results in muscular dystrophy (29,30). Absence of integrin ␣7 leads to muscular dystrophy and pathological changes of the myotendinous junctions (31).…”

Section: Discussionmentioning

confidence: 99%

Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy

Durbeej

Sawatzki

Barresi

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Limb-girdle muscular dystrophy types 2E and F are characterized by skeletal muscle weakness and often cardiomyopathy and are due to mutations in the genes encoding ␤-and ␦-sarcoglycan. We previously demonstrated that loss of sarcoglycans in smooth muscle leads to constrictions of the microvasculature that contributes to the cardiac phenotype. It is unclear how vasculature abnormalities affect skeletal muscle. We injected recombinant ␤-or ␦-sarcoglycan adenoviruses into skeletal muscles of corresponding null mice. We hypothesized that the adenoviruses would not transduce vascular smooth muscle, and we would only target skeletal muscle. Indeed, sustained expression of intact sarcoglycansarcospan complex was noted at the sarcolemma, neuromuscular junction, myotendinous junction, and in peripheral nerve, but not in vascular smooth muscle. Gene transfer of the corresponding deleted sarcoglycan gene preserved sarcolemmal integrity, prevented pathological dystrophy and hypertrophy, and protected against exercised-induced damage. We conclude that vascular dysfunction is not a primary cause of ␤-and ␦-sarcoglycan-deficient muscular dystrophy. In addition, we show successful functional rescue of entire muscles after adenovirus-mediated gene delivery. Thus, virus-mediated gene transfer of sarcoglycans to skeletal muscle in combination with pharmacological prevention of cardiomyopathy constitute promising therapeutic strategies for limb-girdle muscular dystrophies.

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Role for α-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies

Cited by 284 publications

References 48 publications

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

Dysbindin, a Novel Coiled-coil-containing Protein That Interacts with the Dystrobrevins in Muscle and Brain

Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy

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