PITTSBURGH, Feb. 3, 2016 - Researchers at the University of Pittsburgh School of Medicine have shown that the core of the protein clumps found in the brains of people with Huntington's disease have a distinctive structure, a finding that could shed light on the molecular mechanisms underlying the neurodegenerative disorder. The findings were published this week in the Proceedings of the National Academy of Sciences.
In Huntington's and several other progressive brain diseases, certain proteins aggregate to form plaques or deposits in the brain, said senior investigator Patrick C.A. van der Wel, Ph.D., assistant professor of structural biology, Pitt School of Medicine.
"Despite decades of research, the nature of the protein deposition has been unclear, which makes it difficult to design drugs that affect the process," he said. "Using advanced nuclear magnetic resonance spectroscopy, we were able to provide an unprecedented view of the internal structure of the protein clumps that form in the disease, which we hope will one day lead to new therapies."
The gene associated with Huntington's makes a protein that has a repetitive sequence called polyglutamine. In the 1990s, it was discovered that the patients have mutated proteins in which this sequence is too long, yet it has remained unclear how exactly this unusual mutation causes the protein to misbehave, clump together and cause the disease.
"This is exciting because it may suggest new ways to intervene with these disease-causing events," Dr. van der Wel said. "For the first time, we were able to really look at the protein structure in the core of the deposits formed by the mutant protein that causes Huntington's. This is an important breakthrough that provides crucial new insights into the process of how the protein undergoes misfolding and aggregation.
He added Huntington's is one of many neurodegenerative diseases in which unusual protein deposition occurs in the brain, suggesting similar biochemical mechanisms may be involved. Lessons learned in this disease could help foster understanding of how these types of diseases develop, and what role the protein aggregates play.
The team included Cody L. Hoop, Ph.D., Hsiang-Kai Lin, Ph.D., Karunakar Kar, Ph.D., Jennifer C. Boatz, Abhishek Mandal, and Ronald Wetzel, Ph.D., all of the University of Pittsburgh; Gábor Magyarfalvi, Ph.D., of Eötvös University, Hungary; and Jonathan Lamley and Józef R. Lewandowski, Ph.D., of Warwick University, U.K.
The project was funded by National Institutes of Health grants GM112678, AG019322, GM099718 and GM088119; National Center for Research Resources grant RR024153; the Biotechnology and Biological Sciences Research Council; and the Engineering and Physical Sciences Research Council.
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see http://www.medschool.pitt.edu.
Contact: Anita Srikameswaran
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Proceedings of the National Academy of Sciences