Pumping zinc

Why would a cell go to the trouble of destroying perfectly good, newly minted proteins?

JANUARY 3, 2015 22:04

Zinc (photo credit: Wikimedia Commons) — Zinc

(photo credit: Wikimedia Commons)

Why would a cell go to the trouble of destroying perfectly good, newly minted proteins? Weizmann Institute of Science researchers have revealed an unusual cellular mechanism that may be faulty in Alzheimer’s disease. New research at the institute in Rehovot, as well as at Heidelberg University in Germany – which was recently published in Molecular Cell – suggests that this unusual cellular mechanism may, among other things, be faulty in this type of dementia.

Dr. Maya Schuldiner and research student Dr. Shai Fuchs of the Weizmann Institute’s molecular genetics department – working in collaboration with Dr. Marius Lemberg and Dr. Donem Avci in Heidelberg – looked into 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-preserved 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; while 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 Rehovot 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 back-up plan.

High-affinity transporters can go into action to stockpile the nutrient in preparation for coming starvation, but these pumps can’t enable the back-up 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 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 Schuldiner.

VULNERABILITY TO STRESS

Animals are more vulnerable to stress at night and more resilient in the morning, according to a Ben-Gurion University doctoral student in psychology, Shlomi Cohen. Working under the guidance of Prof. Hagit Cohen, director of the stress and anxiety research unit at BGU’s Faculty of Health Sciences, Cohen found that the time – day or night – at which stress occurs significantly affects the behavioral stress response. The researchers’ findings were recently published in the journal Neuropsychopharmacology.

When stressed, rodents released important hormones such as glucocorticoids (cortisol in human and corticosterone in rats) released following brain signaling to the adrenal cortex; and the hypothalamic- pituitary-adrenal or HPA axis) that enable the organism to prepare for, respond to and cope with the acute demands of physical and emotional stressors (fight or flight).

The appropriate corticosterone release, in an amount suitable to the severity of the stressor, enables the body to properly limit stress responses so as to promote recovery. Indeed, inadequate corticosterone release following stress not only delays recovery but can also interfere with the processing or interpretation of stressful information. It is well known that the HPA-axis displays a characteristic circadian pattern of corticosterone release, with higher levels at the beginning of the morning and lower levels at the beginning of the night.

Rats were exposed to stress either at the beginning of the night or at the beginning of the morning. The results clearly showed that the time of day at which traumatic exposure occurred altered the pattern of the behavioral stress response and the prevalence of rats showing an extreme behavioral response (PTSD-like behavioral responses). Rats exposed to the stressor at the beginning the night, when they were inactive, displayed a more traumatic behavioral response, and, conversely, were more resilient to stress exposure in the morning.

Surprisingly, the researchers found that although the basal levels of corticosterone were significantly different between the morning and night, reflecting the expected variation of biological clocks, the magnitude of the HPA axis response to stress was not statistically different between the times.

Rats exposed to the stressor during the night displayed faster post-exposure corticosterone decay and a more pronounced stress-induced decline in neuropeptide Y (NPY) expression in the hypothalamus.

Blocking hypothalamic NPY prior to stress applied in the morning or administering NPY to the hypothalamus prior to stress applied in the night had a significant behavioral effect. The researchers concluded that NPY plays a significant role in granting resilience to stress-related psychopathology.