Scientists Develop Better Way to Assess Alport-related Molecule’s Formation

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by Alice Melão |

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XLAS, COL4A3 or COL4A4 mutations

Japanese researchers have developed a sensitive, less time-consuming and cheaper way to assess the formation of a molecule whose dysfunction is connected with Alport syndrome.

The high-throughput screening method evaluates the functioning of  type IV collagen (Col4). It could increase our knowledge of Alport, paving the way to new therapies, the researchers said.

They published their study in Cell Chemical Biology. The title is “A split-luciferase-based trimer formation assay as a high-throughput screening platform for therapeutics in Alport syndrome.”

“This research should provide a pathway to develop drugs for hereditary diseases, such as Alport Syndrome, that are currently incurable,” Hirofumi Kai, a professor in the Department of Molecular Medicine at Kumamoto University, said in a press release. He was the senior author of the study.

Alport syndrome is an inherited disorder caused by mutations in the genes that encode one of the three chains — α3, α4, and α5 — that form the Col4 protein trimers that are essential for correct kidney function. A trimer is a complex made of three molecules.

If one of the chains is affected, the trimers may not form normally, preventing the normal functioning of Col4.

Scientists have been looking for Alport treatments that could restore Col4 function by facilitating trimer formation. They call such drugs chemical chaperones.

Treatments that have been developed so far have been able to address only the disease’s symptoms, not its cause.

To better analyze Col4 trimer assembly, Kai’s Kumamoto University team developed a new detection system. It is based on a technology called split NanoLuciferase that signals when the three alpha chains interact correctly. The NanoLuc-Col4 system uses α3, α4, and α5 chains fused with small molecules that emit light when close together.

To test the efficacy of the detection method, the researchers used mutated versions of the α5 chain, similar to those found in some patients with Alport syndrome.

In the presence of an abnormal α5 chain, but normal α3 and α4, the system failed to detect a luminescent signal, meaning that Col4 trimers were unable to form correctly. But, when the team used chemical chaperones to help assemble the Col4 trimer, the NanoLuc-Col4 system could detect luminescent signals.

Interestingly, the team observed that the efficacy of each chemical chaperone used to  reestablish Col4 trimers was dependent on the mutation present in the α5 chain. This demonstrated that the detection system is highly sensitive, finding small differences in potential therapies. In addition, it provided further evidence that chemical chaperones have the potential to treat Alport syndrome.

“These results may have a marked impact on therapeutic drug discovery in [Alport Syndrome],” the researchers wrote.

This study was partially funded by the U.S.-based Alport Syndrome Foundation.


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