Sci. Aging Knowl. Environ., 26 March 2003
SAGA of Dying Neurons
Disease-causing protein blocks histone modification
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/12/nw47
Key Words: HAT histone acetyltransferase SLIK
SANTA FE, NEW MEXICO--When lumpy gravy tastes bad, the lumps aren't always what makes it unappealing. Similarly, a neurodegenerative disease in which proteins coalesce might owe its pathology to something other than the molecular sludge. Genetic alterations linked to the disease not only nudge a protein to congregate but also alter its enzymatic function when it's not clumped, according to work presented here at the Enzymology of Chromatin and Transcription Keystone Symposium on 11 March 2003. The results suggest that the protein, which helps control how DNA packs in cells, could spur the disease when its catalytic capabilities falter.
In many neurodegenerative disorders, proteins aggregate in and around neurons. No one knows whether this gunk causes or results from disease. In several afflictions, genes accumulate DNA sequences that add glutamines to the resulting protein; these additions cause the protein to aggregate. For instance, people who bear 35 or more extra glutamines in a protein called SCA7 suffer from spinocerebellar ataxia type 7. Affected individuals lose control of their muscles and suffer retinal degeneration, eventually going blind.
SCA7's cellular role has evaded detection until now. Biochemist Patrick Grant of the University of Virginia in Charlottesville and colleagues discovered clues while studying how changes in DNA packing turn genes on and off. The researchers focused on a group of proteins, collectively called the SAGA complex, which pins acetyl groups to histones, the proteins around which DNA winds. Addition of acetyls relaxes the packing and allows gene-activating machinery to access genes (see "Oh, Behave!" and "Boundary War"). Scientists knew many but not all of SAGA's components, so the researchers sought new protein members. They purified the complex from yeast cells and found that SAGA included the yeast version of SCA7. Additional experiments suggested that the protein is a crucial part of SAGA: The complex disintegrated in yeast cells that lack the SCA7 gene; adding back human SCA7 reunited SAGA.
The team members wondered whether disease-causing glutamine stretches in SCA7 affect SAGA's acetyl-sticking capability. To address that question, they engineered yeast to produce human SCA7 with zero or 10 glutamines--both benign alterations--or a disease-sparking 60 glutamines. Then they purified SAGA and tested its ability to add acetyl groups to histones wrapped up in DNA. SAGA tacked on the chemical tag equally well when it contained SCA7 with either zero or 10 glutamines, but SCA7 with 60 glutamines incapacitated the machine.
The results raise the possibility that altered enzymatic activity in SCA7, instead of or in addition to aggregation, triggers neurodegeneration, says biochemist Robert Roeder of The Rockefeller University in New York City, although additional work is needed to prove that defective acetylation plays a role in the disease. Furthermore, future experiments are needed to show that SCA7 behaves similarly in mammalian cells, say Grant and Roeder. If so, Grant speculates that drugs that block acetyl-removing enzymes might counteract defective SAGA and slow neuron loss. Such treatments might not thin protein lumps, but they could take the foul taste out of neurodegeneration.
--R. John Davenport
March 26, 2003
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Citation: R. J. Davenport, SAGA of Dying Neurons. Sci. SAGE KE 2003, nw47 (26 March 2003)
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