Yeast protein breaks up amyloid fibrils and disease protein clumps differently

November 19, 2012

PHILADELPHIA -- Several fatal brain disorders, including Parkinson's disease, are connected by the misfolding of specific proteins into disordered clumps and stable, insoluble fibrils called amyloid. Amyloid fibrils are hard to break up due to their stable, ordered structure. For example, α-synuclein forms amyloid fibrils that accumulate in Lewy Bodies in Parkinson's disease. By contrast, protein clumps that accumulate in response to environmental stress, such as heat shock, possess a less stable, disordered architecture.

Hsp104, an enzyme from yeast, breaks up both amyloid fibrils and disordered clumps. In the most recent issue of Cell, James Shorter, PhD, assistant professor of Biochemistry and Biophysics, and colleagues from the Perelman School of Medicine, University of Pennsylvania, show that Hsp104 switches mechanism to break up amyloid versus disordered clumps. For stable amyloid-type structures, Hsp104 needs all six of its subunits, which together make a hexamer, to pull the clumps apart. By contrast, for the more amorphous, non-amyloid clumps, Hsp104 required only one of its six subunits.

Unexpectedly, the bacterial version of the Hsp104 enzyme, called ClpB, behaves differently compared to Hsp104. Bacterial ClpB uses all six subunits to break up amorphous clumps and fails to break up amyloid fibrils. Bacteria just ignore these more stable structures, whereas yeast use Hsp104 to exploit amyloid fibrils for beneficial purposes.

"One surprise is that biochemists thought that Hsp104 and ClpB hexamers worked in the same way," says first author and graduate student in the Shorter lab Morgan DeSantis. "This is not the case."

Hsp104 breaks up the protein clumps by "pulling" individual polypeptide chains through a channel that the hexamer forms at its center, recruiting more subunits to the job, as needed. Individual polypeptides emerge on the other side where they can be refolded into active structures. Remarkably, Hsp104 broke up various amyloid fibrils formed by proteins connected to Alzheimer's disease (tau and Ab42), Parkinson's disease (α-synuclein), Huntington's disease (polyglutamine), and even type II diabetes (amylin).

The bad news is that animals do not harbor their own version of Hsp104 and they do not appear to have the protein machinery to break up amyloid clumps as rapidly. But Shorter views this as a possible therapeutic opportunity: "We want to introduce Hsp104 transiently as a therapeutic clump buster and optimize Hsp104 for each type of disease protein." He is heartened by preclinical evidence that Hsp104 rescues neurodegeneration caused by α-synuclein misfolding in a rat model of Parkinson's disease. His lab is now scanning yeast cells to look for the most useful forms of Hsp104.
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Co-authors are Eunice H. Leung, Elizabeth A. Sweeny, Meredith E. Jackrel, Mimi Cushman-Nick, Alexandra Neuhaus-Follini, Shilpa Vashist, Matthew A. Sochor, and M. Noelle Knight, all from Penn.

The research was funded by NIH training grants (T32GM071339; T32GM008275; T32AG000255); NRSA predoctoral fellowships (F31NS079009; F31NS067890); AHA predoctoral and postdoctoral fellowships; an NIH Director's New Innovator Award (DP2OD002177), an Ellison Medical Foundation New Scholar in Aging Award, and Penn Institute of Aging, Alzheimer Disease Core Center, and Diabetes Research Center Awards.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

University of Pennsylvania School of Medicine

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