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Muscular dystrophy through an evolutionary lens

2001; Elsevier BV; Volume: 358; Linguagem: Inglês

10.1016/s0140-6736(01)07038-6

1474-547X

Roland G. Roberts,

Muscle Physiology and Disorders

Roland Roberts grew up in Zambia, and studied in Oxford, London, Cambridge, and Boston before becoming a lecturer in molecular genetics at King's College London. Duchenne muscular dystrophy was first described more than 150 years ago, and results in the progressive wasting of initially apparently normal muscle tissue, with severely disabling consequences. Rational approaches to therapy will entail a thorough understanding of what is going wrong and why; an understanding which I believe can be achieved by standing back from the detailed scrutiny of muscle and examining the underlying system in its biological and evolutionary context. When I started work on Duchenne muscular dystrophy in 1989, the dystrophin protein whose disruption causes the disease had just been identified. Having now worked on dystrophin for a long time, it is difficult to convey how real this tiny entity feels to me. Dystrophin is a slender rod, one end of which is attached to an intricate machine—the dystrophin complex—embedded in the membrane that surrounds each muscle cell. When I think about dystrophin my mind conjures up something that looks like a slightly flexible golf club—only subliminally do I note that one could fit about 10 000 dystrophin rods end-to-end across the head of a pin. The dystrophin complex comprises at least ten proteins, their names (dystroglycan, syntrophins, dystrobrevins, sarcoglycans, &c) perhaps betraying the fact that most of them are distinguished primarily by their association with dystrophin. Dystroglycan moors the complex to the matrix around the muscle cell, and leads a treacherous double life as the receptor for the leprosy bacterium. The four sarcoglycans, each of which is disrupted in a type of muscular dystrophy—the limb-girdle muscular dystrophies—form a neat sub-complex in the membrane. Several of the proteins suggest tantalising vicarious roles in the complex dialogue between the muscle cell and its environment, mediated by molecular messengers such as nitrous oxide, acetylcholine, and metal ions. So what exactly does this nanoscale piece of Meccano do for our muscle cells? Why do young men who don't have these dystrophin rods have such difficulties? And ultimately, what can we do about this situation? 15 years after the dystrophin gene was cloned, these questions remain rhetorical. The basic function of the dystrophin complex remains elusive, the chain of events between the loss of the protein and the development of the disease is still unclear, and therapy is limited. One tack, which has been taken by many scientists, is to look beyond the obvious site of disease to the rest of biology. Dystrophin functions in many parts of the body (some people with Duchenne muscular dystrophy have learning difficulties or night blindness), and some tissues have different versions of the dystrophin complex, with the lead roles taken by distinct closely related proteins. Dystrophin itself has two such understudies, utrophin (a veritable doppelgänger, which is being explored as a therapeutic stand-in for dystrophin itself) and DRP2 (a quarter-sized "dystrophin-lite" present in the brain and peripheral nerves). These complexes together pervade the muscular and nervous systems and many other parts of the body. In 1994, I set out to paint an evolutionary picture—a genealogy—of dystrophin. I visited the marine biology laboratories in Plymouth, UK, and returned with all manner of sea creatures. I found that dystrophin, utrophin, and DRP2 are present in dogfish, with whom we shared an ancestor some 400 million years ago. I therefore investigated some of our more distant relatives; dystrophin was present in sea squirt, scallop, and starfish too. The fruit fly Drosophila melanogaster also has a version (figure). The remaining components of the complex are all present and correct in the fly; it is thus likely that every creeping thing has not only dystrophin, but the entire complex. Perhaps the only way that we can lord it over our invertebrate cousins is that, whereas we have multiple versions of the dystrophin complex tailored to the demands of each organ, flies and worms have taken a one-size-fits-all approach. This simplicity, together with the amenability of these animals as models for human disease, makes invertebrates good experimental aids. The animal that perhaps most aspires to the reductionists' ideal is the soil-dwelling worm Caenorhabditis elegans. The entire developmental pathway, neural wiring diagram, and genetic instruction manual of this creature is known. In the past 3 years, Laurent Ségalat and colleagues have shown that many of the features of our own dystrophin complexes can be reproduced in these minute animals—they even found that the human dystrophin protein can stand in for its worm counterpart. Many of the animals mentioned here have no legs, eyes, lungs, or backbone, but they all have a dystrophin complex. I predict that, despite doing a bit of odd-job work here and there, the dystrophin complex has a single fundamental function. Appreciation of this function will be the key to explaining and treating Duchenne muscular dystrophy.