Potential Drugs to Prevent Amyloid Deposits Discovered

Activating a certain pathway in the endoplasmic reticulum could prevent diseases effected by protein misfolding.

Researchers recently discovered several drugs that have the ability to increase a cell’s ability to find errors in protein production that can lead to amyloidosis diseases.

Researchers believe these drugs could potentially lead to a new intervention approach to disease progression, according to the study published in eLife. In every human cell, proteins fold into the correct shape inside the endoplasmic reticulum (ER).

When the ER finds misfolding errors, it recruits other “chaperone” proteins to catch the misfolded proteins. If the misfolded proteins are not caught before they reach the bloodstream, they can form toxic clusters called amyloid deposits, which can occur in the heart, liver, retina, or other organs, according to the study. These deposits lead to tissue degeneration.

However, there are not always enough chaperone proteins to effectively catch all misfolded proteins before they reach the bloodstream. Researchers are looking at way to activate the ER’s Unfolded Protein Response (UPR), which tells cells to create more chaperone proteins, according to the study.

“We're trying to make these helpers more efficient,” said co-senior author of the study Jeffery Kelly, PhD.

If all of the cells signals of UPR are activated for too long, the cell will die. Researchers previously discovered that the ATF6 pathway could potentially activate only 1 of the 3 signals, which could potentially avert cell death.

Researchers initially discovered 14,000 molecules that could interact with ATF6, and then used multiple gene expression profiling. They found that 79 of the molecules could activate the ATF6 part of the UPR, according to the study.

Transcriptional profiling then lets the researchers examine which molecules were preferentially activating ATF6. The researchers discovered 8 promising “structural families.”

Researchers then attempted to synthesize the compounds to better understand how they were able to activate ATF6. In the next part of their study, researchers discovered that some of the compounds were able to mimic a cell’s normal activation of ATF6 in human liver and plasma cells.

These compounds created additional chaperone proteins. Each of the different compounds activated ATF6 in different ways, and some even caused the activation of other signals of UPR.

The researchers then turned cellular pathways up and down to elicit the ideal response. There was 1 compound that activated ATF6 at 40%, but it created a beneficial response from the ER, according to the study.

Researchers believe that fine-tuning this process could lead to enhanced treatments for human amyloid disease. They plan to continue their work by testing other molecules as drug candidates, and developing models to examine how the compounds work in different diseases effected by protein secretion.

“This is a class of drugs that could also work for diabetes and additional neurodegenerative diseases linked to protein misfolding, like Alzheimer's disease,” Dr Kelly concluded.