Sci. Aging Knowl. Environ., 8 January 2003
Vol. 2003, Issue 1, p. nw5
[DOI: 10.1126/sageke.2003.1.nw5]

NOTEWORTHY ARTICLES

Broken Barrow

Protein involved in neurodegenerative disease loses ability to deliver molecules

Mary Beckman

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/1/nw5

Key Words: nuclear export signals • shuttle

SAN FRANCISCO, CALIFORNIA--Just as a malfunctioning car can plug a freeway exit and prevent a FedEx delivery, mutant proteins in some neurodegenerative diseases instigate pileups within the nucleus that might trap important shipments. The normal versions of these proteins enter and leave the nucleus and might tote other cellular components out, according to work presented here 17 December 2002 at the American Society for Cell Biology meeting. The results hint that the mutant forms might spur illness by detaining key molecules.

Proteins that cause the inherited neurodegenerative disorders known as polyglutamine diseases contain abnormally long stretches of the amino acid glutamine. When the proteins ataxin-1 and huntingtin carry extra glutamines, they cause spinocerebellar ataxia type I (SCA I) and Huntington's disease, respectively. In each disease, oversized proteins collect in the nuclei of some muscle-control neurons and kill them. To investigate potential connections between the protein backup and toxicity, Howell and colleagues watched normal and mutant proteins congregate inside living cells

The team engineered ataxin to glow bright green. To observe the movements of normal ataxin and ataxin with additional glutamines (ataxin-Q84), the researchers created cells that harbored two nuclei apiece. In each cell, they allowed ataxin molecules of one type to fill both nuclei, then they bleached out the fluorescence in one nucleus with bright light. The normal ataxin molecules wriggled from the lit to the bleached-out nucleus, causing it to glow again, but the Q84 version of ataxin remained in place, indicating that the glutamine stretch prevented the defective protein from exiting the nucleus. The team also mixed normal ataxin with messenger RNAs (mRNAs), protein templates that are made in the nucleus and dragged to the cytoplasm, and found that normal ataxin could stick to half a dozen mRNAs of different sizes. The authors propose that ataxin hauls mRNAs out of the nucleus; by restraining the mutant protein, the glutamine stretch would prevent that activity.

Because of similarities between ataxin and huntingtin, the team wondered whether normal huntingtin might also lug important components from nuclei. The researchers looked for a marker of such delivery proteins--a sequence that guides them out called a nuclear export signal (NES). They identified a possible NES, which they then chopped off. Without the NES, twice the usual amount of fluorescent huntingtin stuck in the nucleus of cultured neurons. Because huntingtin binds to a second protein that grabs mRNA but can't leave the nucleus on its own, the authors suspect that the extra glutamines in mutant huntingtin disrupt the exit signal, imprisoning all three molecules.

The work suggests "a novel mechanism" by which polyglutamine proteins might kill neurons, says neuroscientist Christopher Ross of Johns Hopkins University School of Medicine in Baltimore, Maryland. Mutant huntingtin "might gum up the normal mechanism in some way and interfere with [the transport of] mRNA." Additional research should determine whether mRNA shuttling is specific to ataxin, or whether other polyglutamine proteins, including huntingtin, might also waylay messages. Knowing what gets stuck behind a nuclear traffic jam might help untangle some neurodegenerative disorders.

--Mary Beckman

J. L. Howell, H. G. Serra, M. Vandelft, T. Zu, S. Irwin, J. Xia, H. Y. Zoghbi, H. T. Orr, R. Truant, Polyglutamine neurodegenerative disease protein ataxin-1 is a member of a protein complex mediating the nuclear export of specific messenger RNAs. American Society for Cell Biology, 42nd Annual Meeting, 14 to 18 December 2002, San Francisco, California. [Meeting Home Page]


January 8, 2003 Citation: M. Beckman, Broken Barrow. Science's SAGE KE (8 January 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/1/nw5








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