Protein-Hoarding Cells Live Longer with Organizer’s Help

Muscle cell of a long-lived nematode worm: chaperone-rich protein aggregates (green) accumulate and save the cell during aging. [Prasad Kasturi/©MPIB]

Our aging cells become hoarders and accumulate unnecessary proteins. Thus encumbered, they carry out life’s tasks less and less effectively. Worse, cells that burden themselves with toxic protein aggregates age more quickly. In the case of neural cells, protein aggregates are associated with neurodegenerative disorders such as Alzheimer’s, Huntington’s, and Parkinson’s disease.

Like human hoarders, cellular hoarders may benefit if they are given just a little help. In cells, helper proteins make protein aggregates less soluble, relieving pressure on soluble, functional proteins. Helper proteins, or chaperones, play the role of the professional organizer who effectively keeps all the junk in the dumpster.

In the cell, the dumpster—or rather the sequestered protein hoard—is never actually carted away. Still, concentrating harmful proteins in insoluble deposits might be a useful strategy to avoid or postpone neurodegenerative diseases.

This finding emerged from a proteomics study performed by scientists at the Max Planck Institute of Biochemistry. These scientists, led by F.-Ulrich Hartly, Ph.D., used the worm Caenorhabditis elegans as a model organism to analyze the changes that occur in the proteome during a lifespan. After they had profiled more than 5,000 proteins, the scientists were able to see that one-third of proteins had changed in abundance at least twofold during aging. The entire proteome had undergone a severe shift.

Such a shift, the researchers realized, overwhelms the machinery of protein quality control and impairs the functionality of the proteins. The normal relation between different proteins, which is critical for proper cell function, is lost.

Proteome imbalance not only leads to cellular dysfunction, it also accelerates aging, the scientists determined. Evidence that widespread aggregation of surplus proteins can hasten death was presented May 7 in the journal Cell, in an article entitled, “Widespread Proteome Remodeling and Aggregation in Aging C. elegans.”

“[Protein imbalances] are reduced in the long-lived daf-2 mutant but are enhanced in the short-lived daf-16 mutant,” wrote the authors of the Cell article. “Notably, the properties by which proteins are selected for aggregation differ in the daf-2 mutant, and an increased formation of aggregates associated with small heat-shock proteins is observed.”

According to Prasad Kasturi, Ph.D., one of the study's lead authors, these findings indicate that proteome imbalance sets in earlier and is increased in short-lived worms. In contrast, long-lived worms cope much better and their proteome compositions deviate less dramatically from those of young animals.

Surprisingly, the long-lived worms increasingly deposited surplus and harmful proteins in insoluble aggregates, thus relieving pressure on the soluble, functional proteome. However, in contrast to the aggregates found in short-lived animals, these deposits were enriched with helper proteins, which apparently prevented the toxic effects normally exerted by aggregates.

“These findings demonstrate that the cells specifically accumulate chaperone-rich protein aggregates as a safety mechanism. Therefore, the aggregates seem to be an important part of healthy aging,” Dr. Kasturi remarked. Indeed, it is known that insoluble protein aggregates also accumulate in the brains of healthy elderly people.

So far, researchers assumed that neurodegeneration and dementia appear to be mainly caused by aberrant protein species accumulating in aggregates. This assumption may need to be retested.

“Aggregates are not always harmful,” Dr. Hartl concluded. “Finding ways to concentrate harmful proteins in insoluble deposits might be a useful strategy to avoid or postpone neurodegenerative diseases as we age.”