Researchers discover compound that could delay symptoms of Machado-Joseph disease

A team of researchers from the Institute for Research and Innovation in Health at the University of Porto (i3S), in collaboration with the Institute for Research in Life Sciences and Health (ICVS) at the School of Medicine of the University of Minho  (UM) and the Centre for Neuroscience and Cell Biology of the University of Coimbra/Centre for Innovation in Biomedicine and Biotechnology (CNC-UC/CIBB), has identified an experimental molecule that can reduce the severity and delay the onset of spinocerebellar ataxia type 3, also known as Machado-Joseph disease. This is a rare, hereditary and degenerative neurological disease, which 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 ICVS, was published in the journal Advanced Science.

Researchers Alexandra Silva (i3S), Sara Duarte-Silva (ICVS-UM), Ana Luísa Carvalho (CNC-UC/CIBB), Patrícia Maciel (ICVS-UM) and Sandra Macedo-Ribeiro (i3S) are part of the team responsible for the discovery.

Machado-Joseph disease is caused by a mutation in the ATXN3 gene, responsible for producing the ataxin-3 protein, essential for keeping cells healthy. In a normal situation, this protein is dispersed throughout the cell, but when the ATXN3 gene suffers an expansion in a repetitive region, the protein produced retains a long repetition of a single amino acid, glutamine, making it prone to forming clumps that accumulate inside cells, especially in certain areas of the brain and spinal cord. These clumps become toxic and are responsible for the symptoms caused by the disease: difficulty and loss of movement, spasms, imbalance, difficulty speaking, chewing and moving the eyes.

Although there is no agreement on the exact origin of the neurotoxicity, cellular and animal models have shown that the abnormal accumulation of ataxin-3 protein contributes to neuronal degeneration in patients with Machado-Joseph disease. One of the strategies being developed to find treatments is to prevent the formation of toxic aggregates in cells.

In this study, the researchers explored a compound called CLR01, a kind of molecular clamp that has been described as a broad-spectrum inhibitor of abnormal protein accumulation, a phenomenon common in several neurodegenerative diseases. These findings, Sandra Macedo Ribeiro points out, “were very encouraging, showing that CLR01 not only reduced the formation of ataxin-3 protein aggregates, but also disintegrated them, offering hope for future treatments”.

Researchers have 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, or in this case the site involved in the formation of toxic clusters, 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 connects 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 ICVS at the School of Medicine of the University of Minho, it was possible to observe the beneficial effect of CLR01 in cell and animal models mimicking Machado-Joseph disease. Ana Luísa Carvalho, researcher at CNC-UC/CIBB and professor at 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 University of Minho, in addition to the experiments carried out with cells, the team conducted studies on the C. elegans worm, in a model that mimics Machado-Joseph disease, and found that ‘after the administration of this compound, the animals' locomotion improved”.

Likewise, using a mouse model with a mutation for this same disease, the researcher adds, ‘we demonstrated that subcutaneous applications of the CLR01 compound in pre-symptomatic animals significantly delayed the onset of symptoms and their severity.’
In conclusion, Sandra Macedo Ribeiro states, “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. It thus emerges, for the first time, as having strong potential for the future development of new therapies for Machado-Joseph disease". 

These results, the i3S scientist emphasises, “pave the way for the development of new therapies targeting this protein site capable of halting the progression of the disease, using approaches that prevent the formation of clumps in brain cells”. Although still far from being tested in humans, the researchers believe this discovery represents a significant advance in the quest for effective treatments for Machado-Joseph disease