Huntington's Disease

Edited by: Paul Smaglik M. DiFiglia, E. Sapp, K.O. Chase, S.W. Davies, G.P. Bates, J.P. Vonsattel, N. Aronin, "Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain," Science, 277:1990-3, 1997. (Cited in more than 200 papers since publication) Neil Aronin Comments by Neil Aronin, professor of medicine and cell biology, Massachusetts Medical Center, Worcester, Mass. The pathogenic connection between huntingtin the protein and Huntington's the disease has eluded neurologists since 1993.1 Researchers discovered then that a wild-type huntingtin gene had 35 or fewer CAG repeats, but that a mutant form had 36 or more. How a few extra CAG repeats could cause the neurodegenerative disorder drove scientists to examine the relationship between the gene, the protein, and the disease. Neil Aronin and Marian DiFiglia, professor of neurology at Massachusetts General Hospital in Boston explored that relationship by looking for the mutant protein in the brains of patients who had died from the disease. As expected, they found the mutant huntingtin protein expressed there.2 "That was important because then we knew it was not a problem of transcription or translation, but a problem of the protein itself doing some damage." They then started searching for the mutant protein's physical location. About the same time, colleagues in England were conducting a similar hunt in transgenic mice. The groups shared information and antibodies. The group, using an antibody provided by Aronin's team, and Difiglia found the culprit first--aggregations of the mutant protein spread throughout the rodents' brains.3 Aronin soon identified clumps of huntingtin in the human brain, although the aggregations tended to be more limited to specific areas of the brains than in mice. Aronin notes that sharing information with the other group helped both. "We work in a very competitive and cooperative environment in Huntington's disease," Aronin remarks. An "often overlooked detail" of the paper, according to Aronin, is the nature of those huntingtin aggregations. In humans, the protein clumps in two discrete places: in the nucleus to form inclusions and in axons and dendrites to produce dystrophic neurites. "The implication of that is, in the adult form of Huntington's, the dystrophic neurites predominate," Aronin says. He notes that the paper has received many citations because abnormal protein-protein interactions are "fundamental" to neurodegenerative diseases. Many other neurodegenerative diseases, including Alzheimer's, involve similar aggregations of different proteins and protein products. "Here we've described aggregation from gene to protein to potential neuropathology." Aronin and others have since focused on how exactly huntingtin gets into the nucleus. Nobel laureate Max F. Perutz of the Laboratory of Molecular Biology in Cambridge, England, suspects that the mutant protein turns on itself to build flat arrays, or ß sheets outside the nucleus. Also, he adds, the huntingtin generally must be cleaved to get into the nucleus. Aronin suspects that the mutant protein first builds up in axons and dendrites, and only when some unknown enzyme cuts the protein into smaller pieces does the disease ensue. He and others suspect a caspase does that cleaving. Some candidate caspases have been explored in mouse models, but no one has yet implicated a specific protease in humans.4,5 Since this paper, Aronin's group has explored this phenomenon further.6,7 However, they still haven't fingered a specific mechanism or caspase. "One possibility is that the proteosome can't keep up with the amount of abnormal aggregation." These findings collectively provide a clearer picture of how the disease likely works: "The gene produces an abnormal protein, which traffics to parts of the cells where it shouldn't be, forms aggregations, which probably could be removed early on, but over a long period of time, causes the diseases." Despite that clearer picture, the Huntington's puzzle remains far from solved. Aronin notes that the research must take "a few clear-cut directions" to progress. Questions that must be answered include: What is the process by which the proteins aggregate? What can the cell do to rid itself of these aggregates? What other protein-protein interactions lead to pathogenesis? What signaling mechanisms are recruited to lead to cell death? Huntington's Disease Collaborative Research Group, "The number of CAG repeats is 10 to 34 in normal individuals and 37 to 100 in HD patients," Cell, 72:971, 1993. N. Aronin et al., "CAG expansion affects the expression of mutant huntingtin in the Huntington's-disease brain," Neuron, 15:1193-201, 1995. S.W. Davies et al., "Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation," Cell, 90:537-48, 1997. Y.P. Goldberg, "Cleavage of huntingtin by apopain, a proapoptotic cystein protease, is modulated by the polyglutamine trait," Nature Genetics, 13:442-9, 1996. I. Sanchez et al., "Caspase-8 is required for cell death induced by expanded polyglutamine repeats," Neuron, 22:623-33, March 1999. M. Kim et al., "Forskolin and dopamine D-1 receptor activation increase huntingtin's association with endosomes in immortalized neuronal cells of striatal origin," Neuroscience, 89:1159-67, April 1999. M. Kim et al., "Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition," Journal of Neuroscience, 19:964-73, Feb. 1, 1999.

Huntington's Disease

The Scientist Staff

Interested in reading more?

Become a Member of