Neurofilaments, Dystrophin, and Muscular Dystrophy
Abstract & Commentary
Source: Blake DJ, Martin-Rendon E. Intermediate filaments and the function of the dystrophin-protein complex. Trends Cardiovasc Med. 2002;12:224-229.
Cytoskeletal proteins, crucial to the structural and functional integrity of myocytes, include microtubules, microfilaments, and intermediate filaments (IFs). Five classes of IFs are recognized: type I (acidic cytokeratins); type II (basic cytokeratins); type III (desmin and vimentin); type IV (neurofilament triplet proteins); and type V IFs (nuclear lamins). IFs connect diverse parts of the cell, extending from Z-discs to myofibrils, associating with neuromuscular junctions, nuclear membranes, mitochondria, and microtubules.
Dystrophin, an intracytoplasmic protein whose deficiency results in Duchenne muscular dystrophy, comprises part of an extensive membrane-spanning multi-protein complex necessary for muscle membrane structural integrity and signaling. Three multiprotein components comprise this dystrophin-protein complex (DPC): the dystroglycan complex (alpha and beta), the sarcoglycan complex (alpha, beta, gamma, delta, and sarcospan), and the cytoplasmic complex, syntrophin and dystrobrevin (see Figure).
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alpha-dystroglycan lies on the extracellular surface of the muscle membrane, binding laminin in the extracellular matrix and complexing with beta-dystroglycan, the latter spanning the muscle membrane. beta-dystroglycan binds to dystrophin on the intracellular aspect of the muscle membrane and, within the muscle cell membrane, is complexed to sarcoglycan, itself composed of 4 transmembrane glycoproteins (alpha, beta, gamma, delta) and sarcospan. alpha-dystrobrevin, an intracellular protein, forms multiple connections binding to dystrophin, utrophin (a dystrophin-related protein), and the syntrophin protein domain, PSD95-discs large-zona occludens-1 (PDZ). Syntrophins, in turn, bind several proteins including neural nitric oxide synthase (nNOS), stress-activated protein kinase-3 (SAPK), and the skeletal muscle voltage-gated sodium channel (SkM), the last itself spanning the muscle membrane, completing the loop begun with alpha-dystroglycan.
Physical links may exist between the DPC and IFs. Syncoilin, a newly discovered type IV IF protein concentrated at the neuromuscular junction, binds alpha-dystrobrevin in muscle as well as desmin and may assist in the transduction of lateral force in muscle. Desmuslin, a second novel IF protein located at Z-lines of muscle, may also bind alpha-dystrobrevin (demonstrated in vitro but not in vivo) and directly interacts with desmin, which co-localizes to the Z-line. Sequence similarities between desmuslin and chick synemin suggest that, like synemin in the chick, desmuslin may interact with vinculin, a microfilament associated protein, and alpha-actinin, an actin-binding protein. Taken together, an elaborate interconnecting cytoskeletal latticework may exist between alpha-dystrobrevin (and thus the DPC), the IF network, and various cytoskeletal proteins. This interaction may be interrupted in Duchenne dystrophy, Emery-Dreifuss muscular dystrophy, and the various forms of desmin myopathy.
Commentary
Desmin, the first muscle-specific protein to appear during myogenesis, localizes to myotendinous and neuromuscular junctions in skeletal muscle, and, in the heart, to the intercalated discs, the attachment between cardiac muscle cells, and the Purkinje fibers of the conduction system. Surprisingly, myogenesis and myofibrillogenesis proceed despite lack of desmin. However, muscle fibers are more susceptible to injury, with cardiomyopathy and muscular dystrophy developing in desmin knockout mice (Acta Physiol Scand. 2001;171:341-348). Degeneration and fibrosis result from a loss of membrane integrity. In man, desmin myopathy is marked by accumulations of desmin, often in a filamentous fashion, sometimes associated with a desmin gene missense mutation or deletion, and sometimes with an alpha-B crystallin missense mutation (J Child Neurol. 2000;15:565-572). Muscle and cardiac disease are characteristic of these disorders, which may be sporadic or familial. Impaired nonlysosomal proteolysis appears to be responsible for the abnormal accumulation of proteins. Mutant hyperphosphorylated desmin acts as a seed protein for filament aggregation which, when multifocal, is characterized by inclusions such as cytoplasmic or spheroid bodies and, when disseminated, is called granulofilamentous material (Curr Opin Neurol. 1997;10:426-429). As a group, these myopathies are designated "surplus protein myopathies." —Michael Rubin
Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.
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