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Huntington’s diseaseDNADNACAGCAGCAGCAGCAGDNADNADNARNADNADNASPNSPNDNAYour browser does not support the element. is horrible. It is also odd. Illnesses caused by inherited aberrant genes are mostly what geneticists call “recessive”, meaning someone must receive defective versions of the gene involved from both mother and father. Huntington’s, the symptoms of which start with involuntary jerking, mood swings and memory problems, and end with death, is “dominant”—meaning only one parent need be a carrier to pass it on.Since a dominant gene’s ill effects cannot be covered up by a functional version from an unaffected parent, the faulty is generally purged by natural selection. This explains why dominant diseases are unusual. But Huntington’s second, self-preserving, oddity is that unlike most genetic disorders it rarely manifests until well into adulthood, giving plenty of time for it to be passed on. The result is families where half the members are living under premature death sentences.So far, attempts to develop drugs to commute those sentences have failed. But that may change. Steve McCarroll of Harvard University reckons one reason for this failure is that the accepted explanation of how Huntington’s plays out at a molecular level is incorrect. That may have led drug companies up a blind alley. As they outline in this week, he and his colleagues have a better explanation—one that could potentially alter the direction of pharmaceutical research.Only with sequencing did what is happening in Huntington’s start to be understood. People affected are victims of a particularly long chromosomal “stutter”, in which three letters of the genetic code () are repeated over and over again (). The repeated is in the gene which encodes a protein dubbed huntingtin, which is produced in brain cells.For those born with fewer than 36 of these repeats, the stutter does not matter. They are disease-free. Those with 36-39, however, may develop symptoms. And those with 40 or more definitely will. Moreover, the more numerous the repeats, the earlier the symptoms present themselves and the younger the person dies.Given these facts, the generally accepted explanation has been that huntingtin proteins with too many of the extra amino-acid units encoded by the stuttering section are toxic—and the longer the stutter, the more toxic they are. Dr McCarroll begs to differ. He and his colleagues have discovered that for a huntingtin protein molecule to be toxic the underlying gene requires not 36 or more repeats, but 150 or more. Three dozen, he thinks, is the threshold not for toxicity but rather for an instability that causes the number of triplets in the expansion to increase slowly throughout a person’s life.That such expansion happens was noticed in the 1990s, but not widely thought important. Subsequent work showed, however, that patients with mutations in their -repair genes often showed unusually early or late onset of disease. These same -repair genes were also shown to affect the stability of the repeats. This suggested repeat-expansion during a patient’s lifetime might be important.To investigate, the team developed a way to study the matter cell-by-cell in post-mortem brain samples. Using this, they examined almost 600,000 cells (or, strictly speaking, the nuclei of these cells) from brains donated by 50 people who had had Huntington’s and 53 others who had not. They also did a deeper dive into the affected parts of the brains of six further Huntington’s-affected donors.By looking at molecules called messenger s, which carry instructions transcribed from the of genes to a cell’s protein-making machinery, they could tell which genes had been active in each of the cell nuclei they examined. Also, specifically, the transcript of the huntingtin gene told them how long the huntingtin triplet repeat was in that nucleus’s .The team’s analysis showed two things. First, though all sorts of brain cells express huntingtin, of those they were scrutinising only a type called striatal projection neurons (s) manifested profound expansion of the triplet repeat—and it is these cells, not the others, that die in Huntington’s patients. Second, even s have normal gene-expression profiles until their number of repeats exceeds 150, a process that takes decades and is variable from cell to cell. Then all hell breaks loose, as hundreds of other genes suddenly start behaving abnormally. That is more than enough to kill the cell in question.Putting all this together, Dr McCarroll reckons the lack of early symptoms reflects the fact that few cells in younger patients have yet crossed the 150-repeat threshold. The earlier onset of symptoms in those born with more repeats, meanwhile, is because their longer expansions need less time to reach the threshold.Current attempts to develop treatments for Huntington’s are based on the premise that all mutant huntingtin is toxic, and that its suppression with drugs will, therefore, prevent or ameliorate symptoms. Dr McCarroll’s work suggests this sledgehammer approach will actually crack very few nuts, for only a small fraction of cells contain toxic huntingtin at any given moment, and they have it only briefly before it kills them.A better way would be to stop the stuttering from reaching the critical threshold of 150. Since other studies confirm the suspicion that a cell’s -repair mechanism is involved here—specifically, by making mistakes when inspecting the expanded section for potential mutations—a drug that fixed this, Dr McCarroll reckons, might be more likely to help than reducing production of huntingtin.What would really be useful, though, is an explanation of why some cell types are susceptible to triplet-repeat expansion and others are not. Trying to determine that is Dr McCarroll’s next project.
