Protein police
The accumulation of toxic proteins in neurons has been implicated in neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Diseases and multiple sclerosis. Researchers based in Lausanne, Switzerland, have discovered a naturally-occurring cellular process capable of altering the form of these toxic proteins, rendering them harmless and able to resume their normal function.
In order for a protein to do its job in a cell, it must not only have the right chemical composition, but also the right shape. After the protein is manufactured, it undergoes a complex folding process. If the folding is faulty, the protein will be useless or even toxic to the cell. In an article appearing online October 17, 2010 in the journal Nature Chemical Biology, Paolo de los Rios (EPFL) and Pierre Goloubinoff (University of Lausanne) announce the discovery that another protein, Hsp70, can unfold an incorrectly folded protein, giving it a chance to re-fold itself properly and assume its function within the cell.
It’s a kind of natural rehabilitation process for wayward proteins; and it’s one that works well in young tissues but much less effectively as the body ages.
This discovery has potential for clinical applications. In neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, proteins that have become toxic following a faulty folding process start accumulating in neurons. Other proteins, called “chaperones”, including Hsp70, roam the cell carrying out a kind of quality control. When they encounter toxic proteins, one of three things will happen: First, if the chaperones are unable to intervene, the cell will die; alternatively, enzymes will be unleashed to destroy the malformed proteins; and the final possibility is that Hsp70 will kick in and unfold the toxic proteins, giving them the opportunity to re-fold and get the cell back on track. Because this last solution consumes 1000 times less energy than destroying the proteins enzymatically, it is likely a much more effective option for the cell.
The researchers carried out experiments using luciferase, a protein that allows fireflies to emit light. If this protein is folded incorrectly, it won’t glow. To test if Hsp70 was able to restore normal protein function, they introduced Hsp70 and ATP (a cellular fuel) to a tube containing misfolded luciferase. The Hsp70 did its job; the light emitted was proof that the protein had unfolded and managed to refold again correctly.
Because high levels of Hsp70 in a cell can also be toxic, its task of unfolding and re-folding must be isolated and balanced with other cellular processes before it can be used clinically. According to de los Rios and Goloubinoff, it could be many years before this naturally occurring protein police could be used to treat patients suffering from neurodegenerative disease.