June 20, 2012
Molecular Machinery That Pulls Protein Clumps Apart
Amyloid fibers in the brain are a hallmark of many neurodegenerative diseases, including Parkinson's disease, for which there are no effective treatments. These fibers result from aggregation of a specific protein in each disease–in Parkinson's, for example, the aggregated protein is called alpha-synuclein. Although amyloid fibers are implicated in numerous pathologies, they can also play beneficial, protective roles. In yeast, for example, they are associated with increased survival and evolution. In humans, they form biological nanostructures that house pigments and other molecules, and they may also be central to long-term memory.
In a new study published 19 June in the open-access journal PLoS Biology, Martin Duennwald and AnaLisa Echeverria, at the Boston Biomedical Research Institute, and James Shorter, assistant professor of Biochemistry and Biophysics at the University of Pennsylvania, address an urgent need to find ways to promote beneficial amyloid fiber assembly or to reverse its pathogenic assembly, at will.
Amyloid fibers are among the most stable protein-based structures in nature; they are notoriously difficult for cells to break down. Yeast, however, have a disaggregating protein called Hsp104 (also known as a 'molecular chaperone') that can rapidly disassemble amyloid fibers, and this activity is greatly enhanced by another group of chaperones called small heat shock proteins. Humans and other animals lack Hsp104, so can human cells also disassemble these exceptionally stable amyloid fibers? In the new paper, Shorter and colleagues define a mechanism by which small heat shock proteins collaborate with other molecular chaperones to regulate the aggregation and disaggregation of a beneficial yeast amyloid fiber protein, and this throws light on how human cells might do the same thing.
The researchers establish that in the absence of Hsp104, the yeast small heat shock proteins collaborate with other molecular chaperones to slowly disassemble amyloid fibers by removing one subunit at a time from the tips of the fibers. This activity was extremely surprising since the small heat shock proteins and other molecular chaperones are best known for their duties in preventing protein clumping–they were not previously known to disaggregate pre-formed and exceptionally stable amyloid fibers.
"Remarkably, the human small heat shock protein, HspB5, stimulates other heat shock proteins, Hsp110, Hsp70, and Hsp40, to gradually depolymerize amyloid fibers formed by alpha-synuclein, which are implicated in Parkinson's disease" explains Shorter. He adds that, "because monomers [subunits] are released by this system and not toxic oligomers [longer chains of subunits], we believe this is an extremely safe way to dissolve amyloid."
Importantly, the proteins of the amyloid-depolymerase machinery in yeast also exist in humans. Thus, even without Hsp104, human small heat shock proteins can collaborate with other molecular chaperones to disassemble amyloid fibers. These new findings could have therapeutic applications for the treatment of various neurodegenerative disorders, suggest the researchers. The goal is to stimulate the disaggregating machinery in humans where and when needed by increasing the expression of heat shock proteins that should, hopefully, pull apart disease-causing amyloid fibers. The next step will be to boost the activity of the newly discovered amyloid-disaggregating machinery, perhaps with drug-like small molecules, in animal models of neurodegenerative disease.
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