ZAP // Machado Ribeiro S., Maciel P. et al / Advanced Science; Christy Krames, MA, CMI/Wikipedia; 90 Seconds of Science; Healthnews
The study was led by Sandra Macedo Ribeiro (right), from the Institute of Research and Innovation in Health at the University of Porto (i3S), and Patrícia Maciel (left), from the University of Minho (UM)
Machado-Joseph disease is a rare, hereditary and degenerative neurological pathology, which has a significant prevalence in Portugal, and for which there is still no cure or effective therapy.
A team of researchers has identified a new experimental molecule that can reduce gravity and delay the onset of spinocerebellar ataxia type 3also known as .
which was led by researcher Sandra Macedo Ribeirofrom the Institute of Health Research and Innovation at the University of Porto (i3S), and Patricia Macielfrom the University of Minho (UM), with the collaboration of researchers from CNC-UC/CiBB at the University of Coimbra, was recently published in the journal Advanced Science.
Machado-Joseph disease is caused by a change in a gene called ATXN3which produces an important protein for keeping cells healthy, ataxin-3, explain the authors of the study at UC.
In a normal situation, this protein is dispersed throughout the cellbut when the ATXN3 gene undergoes an expansion in a repetitive region, the protein produced retains a long repeat of a single amino acid, the glutamine.
This accumulation makes it more prone to forming clumps that accumulate inside cells, especially in certain areas of the brain and spinal cord.
These clusters become toxic and cause the symptoms caused by the disease: difficulty and loss of movement, spasms, imbalancedifficulty speaking, chewing and moving the eyes.
This is a rare, hereditary and degenerative neurological diseasewhich has a significant prevalence in Portugal, and for which there is still no cure or effective therapy.
Although there is no consensus on the exact origin of neurotoxicity, cellular and animal models show that this is anomalous accumulation of ataxin-3 which contributes to neuronal degeneration in Machado-Joseph disease. Preventing the formation of toxic clusters in cells is one of the strategies being developed to find therapies for this disease.
In this work, researchers explored a compound called CLR01which acts as a kind of molecular tweezers and has been described as a broad-spectrum inhibitor of abnormal protein accumulation, a common phenomenon in several neurodegenerative diseases.
The results, highlights Sandra Macedo Ribeiro, “were quite encouraging, as they show that CLR01 not only managed to reduce the formation of clusters of the ataxin-3 protein, but also disintegrate themoffering hope for future treatments.”
According to the i3S researcher, “the most interesting thing about this study was the discovery of site where the compound CLR01 binds to ataxin-3. This new binding site is located in a region of the protein very far from the region involved in the formation of the clusters”, he explains.
Scientists discovered that CLR01 “works like a key that fits into this distant location, almost as if it were a hidden lock.”
What happens next, explains Sandra Macedo Ribeiro, “is not the immediate closing of the main door, in this case the place involved in the formation of toxic clusters, but rather the activation of a series of levers that move along the protein structure and are able to modify the shape of the main door, causing it to close and thus reducing excessive protein accumulation.”
“In short, the CLR01 turns on like a key in a remote lock and controls the main door from a distance, without ever touching it directly”, concludes the researcher.
In collaboration with teams from CNC-UC/CiBB and UM, it was possible to observe the beneficial effect of CLR01 in cellular and animal models that mimic Machado-Joseph disease.
UC News
Researchers Alexandra Silva, Sara Duarte-Silva, Ana Luísa Carvalho, Patrícia Maciel and Sandra Macedo-Ribeiro
The CNC-UC/CiBB researcher and professor in the Department of Life Sciences at the UC Faculty of Science and Technology, Ana Luisa Carvalhohighlights “the unique effect of CLR01 in reversing neuron dysfunction in cellular models of this rare disease.”
According to the researcher Patricia Macielfrom UM, in addition to experiments carried out with cells, the team carried out studies on the worm C. elegans which mimics Machado-Joseph disease and found that “after the administration of this compound, the animal locomotion improved“.
Likewise, by using a mouse model with a mutation for the same disease, “we demonstrated that subcutaneous applications of the CLR01 compound in pre-symptomatic animals significantly delayed the onset of symptoms and their severity”, adds the researcher.
In conclusion, says Sandra Macedo Ribeiro, “by binding to this new target area of the ataxin-3 protein, the compound CLR01 reduces the tendency of this protein to form harmful deposits, without compromising its normal function in the cells of the nervous system and thus appears, for the first time, with a strong potential for the future development of new therapies for Machado-Joseph disease”.
These results, highlights the i3S scientist, “open the way for the development of new targeted therapies to this new protein site capable of halting disease progression, using approaches that prevent the formation of clusters in brain cells.”
Although they are still far from testing on humans, researchers consider that this discovery represents a significant advance in the search for effective treatments for Machado-Joseph disease.
