Sci. Aging Knowl. Environ., 9 October 2002
Proteins jump in and out of neurodegenerative clumps
Key Words: TATA-binding protein CREB-binding protein GFP FRAP FLIP transcription
Abstract: Like kids in a wrestling match, proteins in some neurodegenerative diseases appear to knot into clumps. Researchers have long thought that the conglomerations' components are stuck, but new live-action footage shows that the proteins do the hokey-pokey; many of them move freely in and out. Further results suggest that this dance reflects cellular custodians delivering defective proteins to a clump-bound cellular incinerator.
Researchers think that the globs in neurodegenerative diseases congeal due to misshapen proteins. For example, long spans of the amino acid glutamine in the mutant huntingtin protein cause it to tangle, and different proteins that contain congealing polyglutamine stretches show up in other neurodegenerative diseases. The clods also harbor cellular cleanup crews--proteasomes that chew up mangled proteins and chaperones that help proteins fold--as well as two proteins that turn on genes, TBP and CBP. No one knows whether or how the aggregates contribute to symptoms. Decades of biochemical tests suggested that they were solid masses that kept proteins from their normal cellular tasks. In July, however, scientists reported that CBP could exit one type of polyglutamine-induced clump. Two research teams decided to watch the clumps in live cells to determine whether cellular cleanup crews could also come and go.
First the groups investigated the mobility of clump-bound components, including one that is involved in breaking down proteins. Stenoien and colleagues attached a blue-glowing tag to ataxin, the protein that causes the polyglutamine disease spinocerebellar ataxia, and they glued a yellow-shining snippet to ubiquitin, which marks misshapen proteins for destruction by the proteasome. By tracking the fluorescence, the researchers saw that ataxin and ubiquitin wriggled into the clumps. To determine whether the proteasome was degrading the newly received ataxin, the team chemically inhibited the protein-munching machine. The concentrations of ubiquitin and ataxin in the clumps rose, suggesting that the degradation system was backing up. Together, the data suggest that the proteasome chews up ataxin within the gobs.
Using similar methods, Kim and colleagues lit up the chaperone HSP70 in cells carrying mutant huntingtin. The researchers found HSP70 jumping in and out of the protein knots. Additional tests suggested that the chaperone was not just visiting the gobs but was trying to fold proteins. Having discovered that apparently beneficial duties occur in the wads, the researchers probed whether the snarls cause trouble as well. The groups followed the movement of two proteins that activate genes to determine whether these essential molecules can escape. The cells' entire CBP complement zipped in and out of protein masses, as did a small amount of TBP. Additional research will determine if the amounts of CBP or TBP caught in the piles contribute to cellular decay.
Protein clumps "can't be viewed as static balls," says neurologist Henry Paulson of the University of Iowa in Iowa City. "The cell is seeing polyglutamine as abnormal and working to lessen the toxicity and destroy it." Researchers might be able to develop treatments that help the cell with the cleanup task, he says. If successful, doctors could put the treatments in, get the clusters out, and turn neurodegeneration around. That's what it's all about.
Citation: M. Beckman, Aggregation Hokey-Pokey. Science's SAGE KE (9 October 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/40/nw136
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