New i3S-led findings signal a potential medical breakthrough
Researchers from i3S and partner institutions have identified an experimental molecule that reduces toxic protein aggregation and may help delay the onset and severity of Machado-Joseph disease
A research team led by the Institute for Research and Innovation in Health (i3S) at the University of Porto, in collaboration with institutions from the Universities of Minho and Coimbra, has identified an experimental molecule capable of reducing the severity and delaying the onset of Machado-Joseph disease. Also known as spinocerebellar ataxia type 3, this rare, hereditary and neurodegenerative condition has a significant prevalence in Portugal and currently has no effective treatment or cure.
Machado-Joseph disease is caused by a mutation in the ATXN3 gene, which leads to the production of an abnormal form of the ataxin-3 protein. Instead of remaining evenly distributed within the cell, the altered protein tends to form toxic aggregates that accumulate in neurons, particularly in the brain and spinal cord. These aggregates are associated with progressive symptoms such as loss of motor coordination, muscle spasms, imbalance, and difficulties with speech, swallowing and eye movement.
The study published in the journal Advanced Science and led by Sandra Macedo Ribeiro, focused on a compound known as CLR01. This molecule acts as a "molecular tweezer” and has previously been described as a broad-spectrum inhibitor of abnormal protein aggregation, a common feature of several neurodegenerative diseases. The researchers found that CLR01 not only reduced the formation of ataxin-3 aggregates but was also able to dismantle those already formed.
According to the research team, one of the most significant findings was the identification of a new binding site where CLR01 attaches to the ataxin-3 protein. This site is located far from the region responsible for aggregate formation, revealing a previously unknown mechanism of action. This discovery opens new perspectives for the development of targeted therapies aimed at slowing the progression of Machado-Joseph disease.
