Hope for Huntington's Disease

The Faculty of 1000 is a Web-based literature awareness tool published by BioMed Central. It provides a continuously updated insider's guide to the most important papers within a range of research fields, based on the recommendations of a faculty of over 1,400 leading researchers. Each issue, The Scientist will publish a list of the 10 top-rated papers from a specific subject area, as well as a short review of one or more of the listed papers. We will also publish a selection of comments on interesting recent papers from the Faculty of 1000's output. For more information visit www.facultyof1000.com. For the first time, a study is suggesting a viable treatment to stop and even reverse Huntington's disease (HD), a lethal disorder afflicting about one of every 15,000 people. This treatment involves a class of drugs already being tested on cancer patients. F1000 Top 10 Neuroscience 1. Y. Zhou et al., "Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 Å resolution," Nature, 414:43-8, Nov. 1, 2001. 2. T. Fukuchi-Shimogori, E.A. Grove, "Neocortex patterning by the secreted signaling molecule FGF8," Science, 294:1071-4, Nov. 2, 2001. 3. C.A. Cowan, M. Henkemeyer, "The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals," Nature, 413:174-9, Sept. 13, 2001. 4. D. Ren et al., "A sperm ion channel required for sperm motility and male fertility," Nature, 413:603-9, Oct. 11, 2001. 5. Z. Zou et al., "Genetic tracing reveals a stereotyped sensory map in the olfactory cortex," Nature, 414:173-9, Nov. 8, 2001. 6. S.H. Scott et al., "Dissociation between hand motion and population vectors from neural activity in motor cortex," Nature, 413:161-5, Sept. 13, 2001. 7. J.H. Morais-Cabral et al., "Energetic optimization of ion conduction rate by the K+ selectivity filter," Nature, 414:37-42, Nov. 1, 2001. 8. D.H. Mauch et al., "CNS synaptogenesis promoted by glia-derived cholesterol," Science, 294:1354-7, Nov. 9, 2001. 9. J.S. Steffan et al., "Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila," Nature, 413:739-43, Oct. 18, 2001. 10. M.T. Christensen, K. Strange, "Developmental regulation of a novel outwardly rectifying mechanosensitive anion channel in Caenorhabditis elegans," Journal of Biological Chemistry, 276:45024-30, Nov. 30, 2001. Typically striking around age 40, HD causes uncontrolled movements, cognitive deficits, and emotional disturbances. Neurons degenerate in certain brain regions. The disease is inevitable if a person inherits a mutant copy of the HD gene in which the first exon contains 40 or more consecutive CAG repeats, each encoding the amino acid glutamine. According to one prominent theory, the gene product, mutant huntingtin (mHTT), folds differently than its wild-type counterpart (the function of which is unknown). As a result, mHTT is cleaved and migrates from the cell's cytoplasm to its nucleus. What happens next has become the focus of intense scrutiny because it is apparently a key to HD pathology. A recent Nature paper reported that mHTT's polyglutamine-containing region binds to the acetyltransferase domains of several transcriptional co-activator proteins and inhibits enzymatic activity.1 Ranked ninth on the Faculty of 1000's December 10th Neuroscience Top 10 list, the paper also disclosed that mHTT reduces acetylation of histones H3 and H4 in a rat cell line. Histone deacetylase inhibitors reversed that process, and when administered to Drosophila models of polyglutamine disease, these inhibitors stopped neuronal degeneration and prevented flies from dying. The Nature paper was largely the fruit of three years' labor by Joan S. Steffan, a transcription expert in the lab of geneticist Leslie M. Thompson. As a postdoc, Thompson helped discover the HD gene in 1993, and she is now an assistant professor of psychiatry and human behavior at the University of California, Irvine. Friends for 20 years, Steffan and Thompson established earlier that mHTT represses gene transcription.2 Such repression has at least two sources. The polyglutamine domain of mHTT interacts with transcriptional co-activators, such as CREB-binding protein (CBP), and deactivates these proteins by sequestering them into insoluble aggregates. In addition, mHTT binds to the acetyltransferase domains of proteins such as CBP, thereby inhibiting histone acetylation. By loosening chromatin structure, histone acetylation enhances gene transcription; by inhibiting such acetylation, mHTT consequently represses transcription. To halt HD's progression, "the ideal approach would be to specifically down-regulate mutant huntingtin--to not have it produced. That's very difficult to do," observes Thompson. "Another approach would be to target the cleavage of huntingtin. That's also extremely difficult to do." The Nature paper suggests a third strategy: counteracting HTT's effect on histones by administering histone deacetylase inhibitors (HDIs). Cancer patients are now receiving HDIs in clinical trials, and Steffan says these drugs have proven safe so far. But trials on Huntington's patients won't begin until the inhibitors are first tested on mouse HD models. The Drosophila is "sufficiently removed" from humans that fly data can't be the sole basis for clinical trials, she explains. Nevertheless, transgenic flies might still serve to screen potential Huntington's drugs, according to J. Lawrence Marsh, the Nature paper's Drosophila expert and a professor of developmental and cell biology at UC Irvine. Though screening is now "somewhat slow and labor-intensive, we're trying to modify things so that it can be more automated, rapid, and simple," he says. Douglas Steinberg (dougste@ATTglobal.net) is a freelance writer in New York. References 1. S. Steffan et al., "Histone deacetylase inhibitors arrest poly-glutamine-dependent neurodegeneration in Drosophila," Nature, 413:739-43, Oct. 18, 2001. 2. S. Steffan et al., "The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription," Proceedings of the National Academy of Sciences, 97:6763-8, 2000.

Hope for Huntington's Disease

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