Full circle to cobbled brain

A biochemical link between certain congenital muscular dystrophies and the associated brain malformation known as cobblestone lissencephaly has been elusive. But it looks as if that link has been found.

Muscular dystrophies are genetic diseases that cause progressive muscle weakness. The best known is that described by Duchenne, which affects boys and is evident from about five years of age, and which results from mutations in the gene encoding a protein called dystrophin. Another subclass is the congenital muscular dystrophies, where muscle weakness is apparent at birth or shortly afterwards. Two of these for which gene mutations have been found are muscle–eye–brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Children carrying the faulty MEB or FCMD genes1,2 suffer from both muscle weakness and 'cobblestone lissencephaly', in which a flaw in neuronal migration results in a brain with a bumpy, cobblestone appearance and loss of the normal folding pattern.

How the two very different muscle and brain defects arise in the same patient has not been known. Now, however, companion papers by Michele et al.3 and Moore et al.4 (pages 417 and 422 of this issue) describe an impressive array of data that points to a common mechanism. To function properly in muscle, dystrophin has to form complexes that include two components, α and β, of another protein, dystroglycan. Each of these has to be appropriately modified by glycosylation — the addition of sugar molecules by glycotransferase enzymes. The β-dystroglycan in the membranous sheath of a muscle cell, the sarcolemma, binds α-dystroglycan; in turn, α-dystroglycan binds to proteins such as laminin in the extracellular matrix. The two papers provide evidence that the defect underlying muscle weakness and brain abnormalities in both MEB and FCMD is disrupted glycosylation of α-dystroglycan (Figs 1 and 2).

Figure 1: Congenital muscular dystrophy and α-dystroglycan3.

In muscle, dystrophin binds both F-actin in the cytoskeleton and the 'dystrophin glycoprotein complex', which includes dystroglycan. α-dystroglycan is a secreted component that lies outside the muscle cell. To function properly, it must be glycosylated — have sugar groups attached — and bind both β-dystroglycan in the cell's membrane, the sarcolemma, and proteins in the extracellular matrix such as laminin. Failure of glycosylation impairs binding to the extracellular matrix, destroying the muscle fibre over time.

Figure 2: Cobblestone lissencephaly and α-dystroglycan4.

In brain development, the dystrophin–dystroglycan complex is present in both of the two principal types of brain cells, glia and neurons. a, During normal development, the top of the cerebral cortex is defined by a basement membrane — the glia limitans — at the end of the radial glial fibres that guide neuron growth. This prevents neurons that form the marginal zone and cortical plate, two layers of the cortex, from migrating out of the brain proper and into the subarachnoid space. b, In cobblestone lissencephaly, failure to glycosylate α-dystroglycan is associated with gaps in the glia limitans, and failure of neurons to organize themselves within the cortical plate and their migration into the subarachnoid space. It remains to be seen whether neuronal motility is also directly affected.

The MEB and FCMD genes both have similarity to genes known to encode glycosyltransferases, although it was unclear which substrates of these enzymes are relevant to the congenital dystrophies. Likely candidates, however, lie in the dystrophin–dystroglycan complex. Mutations in dystroglycan have not hitherto been associated with human disease. But a 'knockout' of dystroglycan in mice proves lethal at the embryo stage. So there have been hints that other proteins cannot substitute for dystroglycan, and that even reduced dystroglycan activity might underlie the human disorders.

Michele et al.3 now provide evidence that reduced (hypo) glycosylation of α-dystroglycan is involved in the two diseases, as well as in a naturally occurring mouse mutant, the myodystrophy (myd) mouse. Muscle biopsies from patients with MEB and FCMD revealed normal patterns of β-dystroglycan but no glycosylated α-dystroglycan. In electrophoresis, the core α-dystroglycan protein showed a shift in mobility, interpreted as a change in apparent molecular weight due to loss of sugar groups. Furthermore, the change in mobility of the α-dystroglycan component was identical for the MEB and FCMD samples, implying that the different glycosyltransferases mutated in these diseases affect the same sugar residues on α-dystroglycan.

The authors further show that the hypoglycosylated α-dystroglycan from patients was impaired in binding proteins such as laminin, agrin and neurexin — all of which are components of basement membrane, the specialized sheet of extracellular matrix that surrounds muscle and other cells. Similar biochemical abnormalities were evident in both the muscle and brain of a myd mouse with a mutation in a gene — the LARGE gene — which again is thought to encode a glycosyltransferase5. Finally, Michele et al. find that defects in neuronal migration in the myd mouse brain are like those seen in MEB and FCMD patients.

In sum, Michele et al.3 show that mutations in three different glycosyltransferases result in similar biochemical abnormalities in α-dystroglycan, with associated changes in muscle tissue. Moreover, the glycosyltransferase mutation in myd mice also results in a neuronal-migration defect that would be expected of a congenital muscular dystrophy in which the brain is affected. One consequence in the mice is a disrupted basement membrane — the glia limitans — of the glial cells that provide essential physical support for neurons in the brain.

Moore et al.4 make the story even more convincing. They took the next logical step: seeing whether knocking out dystroglycan, the proposed target of the glycosylation defect, has the expected effects in the brain. Mice with complete loss of the dystroglycan gene die as embryos, so Moore et al. made a 'conditional' knockout that allowed them to inactivate the gene's expression in glia and brain neurons only.

The result is a viable mutant with normal muscle but brain malformations similar to those seen in MEB and FCMD, and also in Walker–Warburg syndrome, another congenital muscular dystrophy. Most notably, the glia limitans is affected, presumably permitting the overextended migration of neurons in the developing brain (Fig. 2). This is the most important diagnostic feature of cobblestone lissencephaly. The mice also lack the usual fissure between the brain's hemispheres, a characteristic of Walker–Warburg syndrome, and suffer from an overabundance of glia. This last effect could arise in reaction to the loss of basement-membrane integrity, and the consequent inflammatory response, or could be due to the altered development of neurons or glia, or both.

Dystroglycan may also work in the neuromuscular junction6, the structure at which neurons and muscle cells connect and which is similar to the synapses that connect neurons in the brain. So Moore et al.4 went on to look at synaptic function in their knockout mice. Their results from electrophysiological recordings on brain preparations show that the capacity for long-term potentiation, the process thought to underlie learning and memory, is reduced under certain conditions. They suggest that this stems from the effect of impaired dystroglycan in the postsynaptic mechanisms of neurotransmission.

Together, the two reports3,4 describe a powerful 'full circle' of investigation — from known human disease genes, to recognition of similarities between mouse mutants and human disease, to discovery of common features in the disease processes and identification of a pathway that might be involved. Predicting the outcome of genetic-manipulation experiments in mice, and testing those predictions, completes the circle. The exciting part is that this is only the beginning of understanding the neurobiology of the congenital muscular dystrophies. Yet to come is the unravelling of dystroglycan's role in synapse formation in the brain and in the neuromuscular junction, as well as in neuronal migration and synaptic function.


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Correspondence to M. Elizabeth Ross.

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Ross, M. Full circle to cobbled brain. Nature 418, 376–377 (2002).

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