A team of scientists from the University of Porto Institute for Research and Innovation in Health (i3S), in collaboration with the University of Minho (UM) and the Center for Neuroscience and Cell Biology at the University of Coimbra/ Center for Innovative Biomedicine and Biotechnology (CNC-UC/CiBB), has identified an experimental molecule that can reduce the severity and delay the onset of Spinocerebellar Ataxia Type (SCA 3), also known as Machado-Joseph disease. This is a rare, hereditary, and degenerative neurological disease that has a significant prevalence in Portugal and for which there is still no cure or effective therapy. The study, led by Sandra Macedo Ribeiro, from i3S, and co-led by Patrícia Maciel, from UM, was published in the journal Advanced Science.
Machado-Joseph disease is caused by a mutation in a gene called ATXN3, which produces a protein important for maintaining healthy cells, ataxin-3. In a normal situation, this protein is dispersed throughout the cell, but when the ATXN3 gene undergoes expansion in a repetitive region, the protein produced retains a long repetition of a single amino acid, glutamine. This accumulation makes it more likely to form clumps that accumulate within cells, especially in certain areas of the brain and spinal cord. These clumps become toxic and cause the symptoms of the disease: difficulty and loss of movement, spasms, imbalance, difficulty speaking, chewing, and moving the eyes.
Although there is no consensus on the exact origin of neurotoxicity, several cellular and animal models show that it is this abnormal accumulation of the ataxin-3 protein that contributes to neuronal degeneration in Machado-Joseph disease. Preventing the formation of toxic clumps in cells is one of the strategies being developed to find therapies for this disease.
In this study, the researchers explored a compound called CLR01, which acts as a kind of molecular clamp and has been described as a broad-spectrum inhibitor of abnormal protein accumulation, a phenomenon common in several neurodegenerative diseases. The results, Sandra Macedo Ribeiro points out, “were very encouraging, as they showed that CLR01 not only managed to reduce the formation of ataxin-3 protein aggregates, but also to disintegrate them, offering hope for future treatments”.
According to the i3S researcher, “the most interesting thing about this study was the discovery of the site where the CLR01 compound binds to the ataxin-3 protein. This new binding site is located in a region of the protein far removed from the region involved in the formation of the aggregates”, she explains.
The scientists discovered that CLR01 “works like a key that fits into this distant site, 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 site involved in the formation of toxic aggregates, but rather the activation of a series of levers that move along the protein structure and manage to modify the shape of the main door, causing it to close and thus reducing the excessive accumulation of proteins. In short, CLR01 binds like a key in a remote lock and controls the main door from a distance, without ever touching it directly”.
In collaboration with teams from CNC-UC/CIBB and UM, it was possible to observe the beneficial effect of CLR01 in cell and animal models that mimic Machado-Joseph disease. Ana Luísa Carvalho, a researcher at CNC-UC/CIBB and professor in the Department of Life Sciences at UC, highlights “the unique effect of CLR01 in reversing neuron dysfunction in cell models of this rare disease”. According to researcher Patrícia Maciel, from the UM, in addition to the experiments carried out with cells, the team conducted studies on the C. elegans worm that mimics Machado-Joseph disease and found that “after administration of this compound, the animals' locomotion improved”.
Similarly, using a mouse model with a mutation for the same disease, the researcher adds, “we demonstrated that subcutaneous applications of the CLR01 compound in animals that were still pre-symptomatic significantly delayed the onset of symptoms and their severity.”
In conclusion, Sandra Macedo Ribeiro adds, “by binding to this new target site of the ataxin-3 protein, the CLR01 compound reduces this protein's tendency to form harmful deposits without impairing its normal function in the cells of the nervous system and thus emerges, for the first time, with strong potential for the future development of new therapies for Machado-Joseph disease.”
These results, emphasizes the i3S scientist, “pave the way for the development of new therapies targeting this new protein site capable of halting the progression of the disease, using approaches that prevent the formation of clusters in brain cells”. Although still far from human trials, researchers believe this discovery represents a significant advance in the search for effective treatments for Machado-Joseph disease.
i3S with CNC-UC
