Newsdesk Bacterial enzyme promotes recovery after spinal-cord injury A bacterial enzyme could offer new hope for patients with spinal cord injuries, say UK researchers. Elizabeth Bradbury (King’s College London, UK) and colleagues saw “very clear functional recovery” after injecting chrondroitinase ABC intrathecally at the injury site in rats with crush injuries of the cervical dorsal column (Nature 2001; 416: 636–40). Chondroitinase ABC works by degrading chondroitin sulphate proteoglycans (CSPGs) formed in glial scar tissue at the injury site. “CSPGs block the growth of regenerating axons, and this inhibitory activity can be attenuated by removing the molecule’s glycosaminoglycan side chain with chondroitinase ABC”, Bradbury explains. In injured rats, chondroitinase ABC promoted functional recovery and regeneration of both ascending and descending pathways. Walking was restored to near-normal in treated rats, indicating recovery of both locomotor function and proprioception. But sensorimotor function (awareness and
removal of adhesive tape on the forelimbs) did not recover significantly, suggesting that chondroitinase ABC did not promote regeneration of hindbrain sensory nuclei. Chondroitinase ABC also upregulated expression of a nerveregeneration marker protein, growthassociated protein 43. In anaesthetised animals electrical stimulation of the motor cortex evoked large, though delayed, postsynaptic potentials below the lesion site. The authors suggest that “chondroitinase ABC and other potential treatments that affect CSPG production after injury may have therapeutic potential for the treatment of patients with spinal cord injuries”. These experiments are “exceptional in that they combine anatomical, physiological, and behavioural evidence for functional regeneration after spinal cord injury”, says Patrick Anderson (University College London, UK). “It is widely believed that both inhibitory molecules such as CSPGs and the poor regenerative response of many CNS neurons contribute to the failure of
axonal regeneration after spinal cord injury”, he adds. “Curiously, chondroitinase appears to remove inhibitory influences and enhance the intrinsic regenerative response of the injured cells.” Anderson points out that “major problems for patients arise when segments of the cord are completely, or almost completely destroyed”, by contrast to the lesions in the rat experiments. “It is not known yet whether chondroitinase treatment will be effective on much larger lesions.” Anderson notes that other experimental treatments, including vaccination with CNS myelin and treatment with specific antibodies to the nerve-growth inhibitory protein Nogo, have produced axonal regeneration in the spinal cord. “The major significance of all these studies is not that they necessarily offer the immediate prospect of successful treatments for patients but that they offer exciting opportunities to find out what normally prevents axons from regenerating in the CNS.” Dorothy Bonn
Mutated huntingtin disrupts dopamine D2 receptor transcription Expanded huntingtin, the mutation found in patients with Huntington’s disease, prevents the interaction of two transcription factors, which in-turn alters the pattern of gene expression, according to a new study. Huntingdon’s disease is caused by a CAG repeat in the gene for huntingtin, a protein of unknown function. The mutant protein has recently been shown to downregulate a variety of cell proteins, all of which rely on the transcription factor Sp1. Now, Dimitri Krainc and colleagues (Massachusetts General Hospital, MA, USA) have shown that this downregulation occurs because huntingtin binds directly with Sp1, preventing it from interacting with a second transcription factor, TAFII130. One gene affected encodes the dopamine D2 receptor, the expression of which is decreased in the striatum of Huntington’s disease patients. Using the yeast two-hybrid system and cell culture techniques, Krainc’s
group found that expanded huntingtin binds strongly to Sp1, reducing Sp1’s affinity for DNA and interrupting its interaction with TAFII130. This effect was also seen in the brains of both symptomatic and presymptomatic patients with Huntington’s disease, where the mutant protein reduced DNA binding by up to 70%. This “suggests early and persistent inhibition of Sp1 function”, according to Krainc. Overexpression of Sp1 and TAFII130 in cell culture restored normal dopamine D2 receptor expression (Science 2002; published online May 2; DOI: 10.1126/science.1072613). While nuclear-protein aggregates are a hallmark of diseased neurons, their pathogenic role has been questioned in recent years. Krainc showed that Sp1 is not found in the aggregates, which suggests that the soluble form is doing the damage. “We saw all our effects in the absence of aggregates”, he says. “Aggregation
does not seem to be that important [for the pathogenic process].” Leslie Thompson (University of California at Irvine, CA, USA) says these findings help show the importance of transcriptional dysregulation in disease. Once there is a more complete understanding of this mechanism, it may be possible to use small molecules to interfere with the Sp1–huntingtin interaction, or target Sp1-related genes for upregulation. Krainc emphasises that the Sp1 connection is only one pathogenic pathway implicated in Huntington’s disease; there are likely to be others that interact with, or remain entirely separate from, this one. The exciting thing for the molecular geneticist, Krainc says, “is that this is the first time anyone has shown uncoupling of activators from general transcription machinery in a medically relevant context”, which suggests a new model for genetic disease. Richard Robinson
THE LANCET Neurology Vol 1 June 2002
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