Reversing protein aggregations

Reversing protein aggregations

A new study suggests for the first time a novel form of protein aggregation that is both reversible and has positive physiological consequences for cells. The work is published in the journal Molecular Cell.

"Most of the functions within our cells are carried out by proteins. But when these proteins aggregate, they produce a 'blob' that renders them inactive," senior author says. "Protein aggregation tends to increase with age and leads to a number of human diseases, particularly those resulting in neurodegeneration."

"Moreover, when proteins adopt an erroneous configuration -- when they're misfolded -- the cells attempt to take the clumps apart, or to pile them up at particular locations in the cell, to minimize their toxic effect," another author says. "This process has been linked to the development of a number of neurodegenerative conditions, such as Alzheimer's, Parkinson's and 'mad cow' diseases."

The new study examines an entirely different type of protein aggregation, which may provide a new mechanism with which to regulate the activity of genes according to changes in the cell's environment.

The AMP-activated protein kinase (SNF1 in yeast) is a central regulator of metabolism that is activated when energy is depleted. Authors found that SNF1 activity in the nucleus is regulated by controlled relocalization of the SNF1 activator Std1 into puncta.

The research for the study emerged serendipitously. While the author was studying the metabolism of sugars in yeast cells and noticed that a tagged version of the protein he was observing -- Std1 -- formed a bright splotch outside the cell's nucleus whenever glucose was added to the cells.

In other words, Std1, which is usually present in the cells' nuclei, where the genome resides, ended up in an aggregation outside of the nuclei.

"We wondered whether this protein aggregation would change according to different conditions in the microenvironment of the cell," senior author says. "And indeed, when conditions changed again and glucose was depleted, the aggregate dissolved and the Std1 protein could be seen again in the nucleus. Std1 plays a role in responding to different sugars in the growth medium, so the reversible aggregation and dissolution of Std1 allowed the cell to respond quickly to varying levels of sugar abundance."

Glucose regulates the process through the activity of the previously uncharacterized protein kinase Vhs1 and its substrate Sip5, a protein of hitherto unknown function. Phosphorylation of Sip5 prevents its association with Std1 and triggers Std1 accretion. Reversible Std1 puncta formation occurs under non-stressful, ambient conditions, creating non-amyloid inclusion bodies at the nuclear-vacuolar junction, and it utilizes cellular chaperones similarly to the aggregation of toxic or misfolded proteins such as those associated with Parkinson’s, Alzheimer’s, and CJD diseases.

Bad -- and good -- for you

The study also suggests that not all protein aggregates are "bad for you." Some play important physiological and regulatory roles. According to the study, the "molecular chaperones" that have been found to fuel many neurodegenerative diseases may have originally been intended to regulate the buildup of non-pathological proteins.

"These results could open the way for possible future treatments that may try to change the aggregation from irreversible to reversible," senior author says. "If we can find out how to turn an irreversible aggregation into a reversible one, it would be possible to treat neurodegenerative diseases and reverse the effect of the aggregates.

"In other words, it may still be possible to reconstruct an egg from an omelette," senior author observes.

The researchers are currently examining what makes the same protein behave differently under different conditions.