September 19, 2014

A New View of What Stress Can Do

The misfolded proteins that accumulate in ALS and Alzheimer's appear to be the result of cells' response to stress.

The 100 trillion or so cells that make up our bodies operate much like miniaturized factories — resources come in; energy is used; and something is ultimately produced, generally in the form of proteins. Our genes serve as the blueprints for these proteins, and similar to a factory, the production process is regulated at every step.

But when we are stressed, a new study from Duke University has found, things can go wrong on the factory floor. Proteins are misfolded, or not folded at all. Researchers hope the discovery may help us better understand diseases like Alzheimer’s, ALS, Huntington’s, Parkinson’s, and type 2 diabetes which are the result of abnormal protein production.

Similar to the alarm signaling a jam in the conveyor belt of a factory, the cell signals a slowdown in production so that the abnormal proteins can be properly discarded.

Our cells are able to recognize when proteins are not being produced according to plan, the Duke researchers found. During times of stress, accumulation of these abnormally shaped proteins triggers a response in which the cell reshuffles its work flow. This is an entirely new mechanism for how the cell responds to stress, according to Christopher Nicchitta, one of the researchers.

Cells can actually remodel the organization of their protein production machinery in order to compartmentalize work load. When cells are starved or exposed to unusually high temperatures, they become stressed and produce abnormally shaped proteins. Similar to the alarm signaling a jam in the conveyor belt of a factory, the cell begins an “unfolded protein response” (UPR). This signals a slowdown in production so that the abnormal proteins can be properly discarded.

Cellular stress also appears to initiate other quality control mechanisms. For example, the team found that stressed cells move their production machinery from the usual production site out to a distant region of the cytoplasm for storage. When these cells are no longer in a state of stress, this machinery is returned to the production site.

In some cases, simply slowing down production via the UPR may be sufficient for dealing with problems that arise during stress. However, when abnormal proteins rapidly accumulate, more drastic measures will be needed. The team believes this compartmentalized shut-off provides this more drastic form of control.

Even more interesting, they found that the newly identified mechanism only affected a subset of proteins during production. This subset includes membrane-bound proteins and those that are secreted from the cell, such as hormones. This was a surprising finding because these are the very proteins that typically set off the stress response in the first place.

While researchers aren’t yet sure what this means, they are now searching for specific factors that determine which cellular mechanism is triggered during a given stressful condition and why. These insights, they hope, will ultimately help develop therapies for the suite of degenerative conditions that arise from the accumulation of abnormally shaped proteins.

The study is published in the journal Cell.
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