Living cells are like miniature factories, responsible for the production of more than 25,000 different proteins with very specific 3-D shapes. And just as an overwhelmed assembly line can begin making mistakes, a stressed cell can end up producing misshapen proteins that are unfolded or misfolded. Now Duke University researchers in North Carolina and Singapore have shown that the cell recognizes the buildup of these misfolded proteins and responds by reshuffling its workload¹, much like a stressed out employee might temporarily move papers from an overflowing² inbox into a junk drawer.

 

The study, which appears Sept. 11, 2014 in Cell, could lend insight into diseases that result from misfolded proteins piling up, such as Alzheimer's disease, ALS, Huntington's disease, Parkinson's disease, and type 2 diabetes³.

 

"We have identified an entirely⁴ new mechanism⁵ for how the cell responds to stress," said Christopher V. Nicchitta, Ph.D., a professor of cell biology at Duke University School of Medicine. "Essentially⁶, the cell remodels⁷ the organization of its protein production machinery⁸ in order to compartmentalize the tasks at hand."

 

The general architecture and workflow of these cellular⁹ factories has been understood for decades. First, DNA's master blueprint¹⁰, which is locked tightly in the nucleus¹¹ of each cell, is transcribed¹² into messenger RNA or mRNA. Then this working copy travels to the ribosomes standing¹³ on the surface of a larger accordion-shaped structure called the endoplasmic reticulum (ER). The ribosomes on the ER are tiny assembly lines that translate the mRNAs into proteins.

 

When a cell gets stressed, either by overheating or starvation, its proteins no longer fold properly. These unfolded proteins can set off an alarm -- called the unfolded protein response or UPR -- to slow down the assembly line and clean up the improperly¹⁴ folded products. Nicchitta wondered if the stress response might also employ other tactics to deal with the problem.

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