Mechanism in Neurodegenerative Disease: Clogged Cellular 'Garbage Disposal'

Release Date:
Karin Jegalian, NIGMS
People with brain-ravaging diseases like Alzheimer's, Parkinson's, and Huntington's all have nerve cells that contain clumps of misfolded, damaged proteins. Scientists funded by the National Institute of General Medical Sciences (NIGMS) have shed new light on how such clumps cause so much harm.
Richard I. Morimoto, Ph.D., of Northwestern University in Evanston, Illinois, led a team that examined the effect of a mutant protein involved in Huntington’s disease on a crucial piece of cell machinery called the proteasome. This cellular "garbage disposal" chops up proteins that have outlived their usefulness, but a mutant form of a natural protein named Huntingtin permanently latches onto the proteasome and brings its operation to a halt. As a result, molecules that should be degraded instead accumulate, poisoning the cells that house them.
The research is reported in the October 27 issue of The EMBO Journal, published by the European Molecular Biology Organization.
Abnormal forms of Huntingtin and other proteins associated with neurodegenerative diseases contain extra copies of a protein building block named glutamine, which form long "tails." In recent years, researchers had suggested that these glutamine tails might block proteasome function. Recent work out of the lab of Alfred L. Goldberg, Ph.D., at Harvard Medical School in Boston, Massachusetts, hinted that the tails may clog the central pore of proteasomes. The long glutamine strands also prevent proteins from folding correctly and prompt them to clump together.
"We've known for a long time that the abnormal proteins produced in neurodegenerative diseases aggregate, but now we’ve built a new link in the chain of logic for why such aggregation ultimately kills neurons," said Jeremy M. Berg, Ph.D., NIGMS Director. "The findings not only reveal a possible molecular mechanism for neurodegenerative diseases, they may also point to methods to prevent or treat them."
NIGMS supports basic biomedical research that lays the foundation for advances in disease diagnosis, treatment, and prevention. It is part of the National Institutes of Health, U.S. Department of Health and Human Services.
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References: Holmberg CI, Staniszewski KE, Mensah KN, Matouschek A, Morimoto RI. Inefficient degradation of truncated polyglutamine proteins by the proteasome. EMBO J 23:4307-18, 2004.
Venkatraman P, Wetzel R, Tanaka M, Nukina N, Goldberg AL. Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Molecular Cell 14:95-104, 2004.
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