Each of these diseases can be traced to a different flawed gene, but each shares a common problem in its DNA -- instructions for producing the amino acid glutamine are repeated excessively along a given stretch of a gene coding for an important protein. In normal proteins, the sequence of three nucleotides that constitutes glutamine -- cytosine, adenine, and guanine, or CAG -- is often repeated 15 to 20 times, but in the mutant proteins the repeats increase in number to 50 or even 100, with earlier onset and greater severity of the particular disease linked to higher numbers of the trinucleotide repeats. The cause for the increased repeats is not known.
Now, scientists have discovered that the proteins with glutamine expansions, which appear to function well in most respects, have a new and dangerous characteristic that their normal counterparts do not. In some neurons, the CAG-repeat proteins accumulate in the nuclei of the cells, aggregating into insoluble masses that can crowd and eventually fill much of the nuclear space. And once this aggregation has begun, the mutant proteins appear to recruit normal versions of the protein into the growing mass, called an inclusion, further exacerbating the problem.
"These aggregated proteins take over a significant fraction of the space in the nucleus and at some point will begin to shut down nuclear processes critical to the cell's survival," says Randall N. Pittman, PhD, an associate professor of pharmacology and senior author on the Neuron paper, which deals with Machado-Joseph disease. "What's emerging from these studies is a recurring theme. In several important neurodegenerative diseases, we are seeing these proteins aggregating abnormally and forming insoluble complexes in the nuclei of certain brain cells. It's a pathological hallmark that suggests that a single disease mechanism may underlie this group of afflictions."
The new results suggest several directions for future research, according to Pittman. Because the proteins involved are produced in cells throughout the body, including the brain, one question scientists would like to be able to answer is why the aggregations occur only in selected populations of neurons. How and why do the proteins accumulate in the nucleus, instead of passing back and forth into the cytoplasm across the nuclear membrane? How is the mutant protein able to recruit the normal protein -- and perhaps other nuclear proteins -- into the inclusions? And what are the specific links between the aggregates and neuronal dysfunction and death? Potential therapies for the diseases could be pursued along each of these lines of inquiry.
The lead author on the Neuron paper is former Penn research associate Henry L. Paulson, MD, PhD, now at the University of Iowa. With Pittman, coauthors at Penn include Matthew K. Perez, MS; John Q. Trojanowski, MD, PhD, a professor of pathology and laboratory medicine; Sonal S. Das, BS; and Kenneth H. Fischbeck, MD, a professor of neurology. Coauthors at other institutions include Y. Trottier and J.-L. Mandel at the Institut de Genetique et de Biologie Moleculaire et Cellulaire, France; and S.H. Subramony and P. Vig at the University of Mississippi, Jackson.
Funding for the work was provided by the National Institutes of Health, the Howard Hughes Medical Institute, and the American Academy of Neurology.
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