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A new class of molecules that could lead to drugs for neurodegenerative diseases such as Alzheimer’s was reported last month in the open-access journal eLife.
The new chemicals could serve as templates for developing treatments for Alzheimer’s, Huntington’s and prion disease.
For proteins in a cell, having a correct 3D structure is essential. Chaperones are molecules that assist with protein folding and ensure proteins group together as they should. If protein folding is disrupted, it causes stress to the cell and triggers an unfolded protein response. One approach to treating neurodegenerative diseases is to use ‘chemical chaperones’ that prevent the build-up of misfolded proteins and reduce cell stress.
“A key obstacle to identifying chemical chaperones is the lack of tests for monitoring incorrect protein folding,” explains senior author Seiichi Oyadomari, from the Institute of Advanced Medical Sciences, Tokushima University, Japan. “In this study we screened hundreds of thousands of molecules using a unique test that measures the unfolded protein response as an indicator of the protein folding disruption.”
The team tested more than 200,000 chemicals to see which ones affected the unfolded protein response. Four of the top 10 chemicals that caused the most potent response had a common structure. One of these, IBT21, was selected for further experiments.
First, they looked at whether IBT21 could prevent the unfolded protein response triggered by a toxin called tunicamycin. Remarkably, they found that IBT21 blocked the unfolded protein response almost completely, by 91.8%. IBT21 was also much more powerful at blocking this response than a known chemical called azoromide that improves endoplasmic reticulum (ER) protein folding ability and activates ER chaperone capacity.
Next, they studied whether IBT21 could reduce protein build-up in cells treated with the tunicamycin toxin. In cells with fluorescently labelled proteins, treatment with tunicamycin caused proteins to accumulate, showing as a fluorescent glow throughout the cell. But when they added IBT21, the intensity of the fluorescence was reduced. This shows that IBT21 prevents the build-up of improperly folded proteins.
Finally, the team looked at whether IBT21 could protect cells against prion disease. Prion disease is a neurodegenerative disorder caused by the accumulation of an abnormally folded prion protein. Cells grown with a mutated prion protein are less viable and unable to grow. However, treatment with a small dose of IBT21 restored the cell growth and the cells recovered.
“Taken together, our results show the promise of IBT molecules as potent chemical chaperones that can prevent diseases resulting from protein aggregation,” concludes Oyadomari. “IBTs might be useful as diagnostic tools for identifying protein deposits in neurodegenerative diseases and as future treatments for Alzheimer’s, Huntington and prion diseases.”
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