Sci. Aging Knowl. Environ., 1 September 2004
Vol. 2004, Issue 35, p. nf80
[DOI: 10.1126/sageke.2004.35.nf80]

NEWS FOCUS

Stuck in the Craw

Parkinson's proteins choke cell's recycling system

Mitch Leslie

http://sageke.sciencemag.org/cgi/content/full/2004/35/nf80

Nuclear waste and plastic bottles might last forever, but proteins don't. Cells chop them up and reuse the pieces. A new study suggests that warped proteins found in rare forms of Parkinson's disease (PD) jam cellular recycling machinery. The results might explain why protein clots amass in common types of PD.

A cellular garbage masher called the proteasome minces some damaged or retired proteins, and enzyme-filled bags called lysosomes dissolve others. Lysosome-powered "self-eating"--known as autophagy--occurs in multiple ways (see Cuervo Perspective). Membranes within the cell can engulf some of its contents and tote the dross to a lysosome. But the cell can also mobilize proteins called chaperones to orchestrate more selective disposal. They grab proteins ready for recycling and usher them to the lysosome's membrane, where the proteins attach to receptors and slip inside. Mutations that prevent the proteasome from snarfing scarred proteins could contribute to PD (see "Deadly Giveaway").

But faulty autophagy might also promote the disease. For instance, hindering lysosomal activity in cultured cells increases the buildup of {alpha}-synuclein, the protein that amasses in neurons of PD patients. Cell biologist Ana Maria Cuervo of Albert Einstein College of Medicine in New York City and colleagues wanted to clarify whether membranes or chaperones ensnare {alpha}-synuclein and whether glitches in lysosomal uptake of the protein contribute to PD.

To a solution containing lysosomes, the scientists added one of two proteins that compete with {alpha}-synuclein for lysosome-receptor attachment. Both reduced the amount of {alpha}-synuclein destroyed in the lysosomes, whereas a molecule that doesn't latch onto the receptor had no effect. When the team altered the segment of {alpha}-synuclein that attracts chaperones, the amount of protein crossing into lysosomes plummeted. Together, these findings show that chaperones corral most of the {alpha}-synuclein that gets recycled in lysosomes.

The team then tested two variants of {alpha}-synuclein that cause rare, inherited forms of PD. The molecules stuck to the lysosome receptor much more tightly than did the normal form, but fewer of the altered proteins entered the organelles. Furthermore, the addled versions impaired the lysosome's breakdown of other proteins. The findings could explain why {alpha}-synuclein clumps in rare kinds of PD, says Cuervo: Cells can't get rid of it. And by blocking the lysosome, {alpha}-synuclein might impede the disposal of other worn-out proteins. In the more common type of PD, {alpha}-synuclein could congeal if other proteins clog lysosomes, Cuervo hypothesizes. The researchers are looking for such proteins.

Researchers have focused on how proteasome glitches abet PD, says neuroscientist Seung-Jae Lee of the Parkinson's Institute in Sunnyvale, California. But "this paper adds to the evidence that lysosomes and autophagy are also important." Even normal {alpha}-synuclein can incur damage from reactive oxygen species or stick together, says neuroscientist Ted Dawson of Johns Hopkins University School of Medicine in Baltimore, Maryland. Scientists should find out whether these altered proteins adhere to lysosomes and hamper protein degradation, he says. Further work on how cells cannibalize proteins might eventually reveal ways to make {alpha}-synuclein biodegradable.


September 1, 2004
  1. A. M. Cuervo, L. Stefanis, R. Fredenburg, P. T. Lansbury, D. Sulzer, Impaired degradation of {alpha}-synuclein by chaperone-mediated autophagy. Science 305, 1292-1295 (2004). [Abstract/Free Full Text]
Citation: M. Leslie, Stuck in the Craw. Sci. Aging Knowl. Environ. 2004 (35), nf80 (2004).








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