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.
University of Pennsylvania School of Medicine: http://www.uphs.upenn.edu/news/
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Researchers were surprised by what they found when they sandwiched a drop of water between two layers of an unusual two-dimensional material called graphene.
Scientists at Cern are suggesting they could soon detect miniature black holes, proving the existence of parallel universes and disproving the big bang theory of the creation of the universe.
The Curiosity rover makes a detection of nitrogen compounds which provide further evidence that ancient Mars would have been a habitable world.
Wild animals can predict earthquakes several weeks before they strike, and motion-activated cameras that track their movements could be adopted in quake-prone countries as an affordable early warning system, scientists said on Tuesday.
GENEVA (Reuters) - Scientists at Europe's CERN research center have had to postpone the imminent relaunch of their refitted 'Big Bang' machine, the Large Hadron Collider, because of a short-circuit in the wiring of one of the vital magnets.
Images taken by NASA's Dawn spacecraft show that a mysterious bright spot on dwarf planet Ceres could be a plume of water spurting from a deep, icy crater
Using seismic vibrations from earthquakes around the world, they are figuring out what Earth looks like below the surface
In honor of a very special Pi Day, enjoy this map that explores the human-made and natural structures that come closest to a perfect circle
The moon has a more complex history than previously thought with at least nine subsurface layers, results from ground-penetrating radar aboard China’s Yutu lunar rover shows, scientists said on Thursday.
Scientists at the CERN physics research center said on Thursday the mystery dark matter that makes up 96 percent of the stuff of the universe will be a prime target for their souped-up Large Hadron Collider (LHC) in the coming years.