LA JOLLA, Calif.—In a new study reported on this summer, scientists at The Scripps Research Institute (TSRI) identified drug candidates that can boost a cell’s ability to catch the “typos” in protein production that can cause a deadly disease called amyloidosis.
“This study reveals a new approach to intervene in human disease,” said Luke Wiseman, assistant professor at TSRI and co-senior author of the new research with Jeffery Kelly, the Lita Annenberg Hazen Professor of Chemistry at TSRI.
The research was published today in the journal eLife.
As TSRI explained, every human cell houses a little factory called the endoplasmic reticulum (ER), where proteins are folded into their proper three-dimensional shape before exiting a cell. When the ER notices a typo in these proteins—a misfolding event—it recruits chaperone proteins to catch the misfolded proteins before they enter the bloodstream and form toxic clusters, or amyloid. Amyloid deposits in the heart, liver, retina or other organs in amyloidosis diseases lead to the degeneration of these tissues.
But there are not always enough chaperones to catch all misfolded proteins. To fix this, scientists are looking at possible strategies to activate the ER’s unfolded protein response (UPR), a signaling network that tells cells to produce more chaperone proteins to enhance editing or protein quality control.
“We’re trying to make these helpers more efficient,” said Kelly, who also serves as chairman of the Department of Molecular and Experimental Medicine and is a member of the Skaggs Institute for Chemical Biology at TSRI. But there’s a catch to this approach—the cell will die if all three signaling “arms” of the UPR are activated for too long.
However, a 2014 study from the Wiseman and Kelly labs indicated there may be a way to activate just one “arm” of the UPR, the ATF6 pathway, to catch misfolded proteins without triggering cell death. For the new study, the researchers teamed up with TSRI’s Molecular Screening Center, on the institute’s Florida campus, to pursue this potential approach to developing new therapies.
“Now we can fine-tune the ER quality-control process,” said Lars Plate, a TSRI research associate who was co-first author of the study with Christina B. Cooley, a TSRI research associate at the time of the study, who is now an assistant professor at Trinity University.
The next steps will be to test several other small molecules as potential drug candidates and develop models to study these compounds in different diseases where protein secretion plays a role.
“This is a class of drugs that could also work for diabetes and additional neurodegenerative diseases linked to protein misfolding, like Alzheimer’s disease,” said Kelly.
