Alzheimer’s: Faulty zinc pump?

Dr. Maya Schuldiner and research student Dr. Shai Fuchs of the Weizmann Institute's Department of Molecular Genetics, working in collaboration with Drs. Marius Lemberg and Donem Avci of Heidelberg University, studied presenilin, a human protein mutated in a familial form of early-onset Alzheimer's.

To investigate the mechanism of this protein, the researchers looked to the ancestor of presenilin, a yeast protein they identified as Ypf1 (for yeast presenilin fold1), which has been well-conserved throughout evolution. When they removed Ypf1 from the yeast cells, the result was excess quantities of a protein whose role is to pump zinc -- an essential metal -- into the cell. The puzzling thing was that, although there are two proteins for pumping zinc into the cell, only one was affected. The one increased is a "turbo," or high affinity, pump; the second, unaffected protein is more of a "workaday," low affinity pump. Like presenilin, Ypf1 is a protease -- a protein that degrades other proteins -- so the researchers concluded that its function is to rid the cell of the "turbo" zinc transporters.

In fact, they realized they were looking at a sort of two-pump system, which had first been described several years ago by the Weizmann Institute's Prof. Naama Barkai. The low-affinity nutrient pumps may not be as efficient at bringing nutrients into the cell, but they are very sensitive to changes in those nutrients; when levels drop, they enable the activation of a backup plan. High-affinity transporters can go into action to stockpile the nutrient in preparation for coming starvation, but these pumps can't enable the backup plan. In this scenario, healthy cells should work most of the time on the workaday pumps, only allowing the turbo pumps to reach their outer surfaces in times of need.

The researchers asked how excess turbo pumping on the cell's surface would affect its ability to prepare for scarcity. Indeed, Ypf1-deficient cells were very slow to sense the nutrient's lack, so they performed poorly during zinc starvation and took longer to recover. And more than zinc pumps are affected: the research showed that in the absence of Ypf1, high-affinity transporters for many other nutrients are deregulated.

"Continually producing high-affinity transporters and then degrading them is a sort of double-safe mechanism that cells evolved to ensure that levels of vital nutrients like zinc remain as stable as possible within the cell," says Dr. Fuchs. "Though we still don't know exactly how the mechanism in humans is tied to Alzheimer's, there is some interesting evidence that zinc transport in particular, and metal transport in general, could play a pivotal role in disease onset and progression." "We are excited that this new clue may open up fresh directions for thinking about the causes of Alzheimer's disease, as these are still not well understood," says Dr. Schuldiner.