In the development of some birth defects, as well as in cancer and other common diseases, the functioning of cellular condensates is crucial. These aggregates are a form of organization within cells that resemble tiny protein-rich droplets that fuse, divide, or dissolve.
These proteins display, in their sequence, characteristics that work as directional markers that tell them which condensate they should move to. When labels get messed up, proteins can end up in the wrong condensate.
According to an international team of researchers working in clinical medicine and basic biology, this mislocalization (or disorganization) of proteins may be the cause of many rare or incurable diseases.
Condensates resemble tiny protein-rich droplets that coalesce, divide, or dissolve within the cell.
In fact, researchers led by the Max Planck Institute for Molecular Genetics (MPIMG) and the Charité Institute for Medical and Human Genetics – Universitätsmedizin Berlin, with the collaboration of the Biomedical Research Institute (IRB) of Barcelona, ​​​​the Hospital Universitario Schleswig-Holstein (UKSH) and other collaborators around the world, have identified the underlying cause of a rare serious disease called brachyphalangia, polydactyly and tibial aplasia/hypoplasia syndrome (BPTAS for its initials in Spanish). English).
In this case, the disorder is caused by a genetic change that causes an essential protein to migrate to the nucleolus, which is a large blob of protein in the cell’s nucleus. Among the effects that this disease can have are various malformations in the extremities.
“We discovered a new mechanism that may be involved in a wide range of diseases, including hereditary diseases and cancer”, says Denes Hnisz, leader of the MPIMG research group, when presenting the study published in Nature.
The mechanism may be involved in a wide range of unresolved diseases.
“In fact, we discovered more than 600 similar mutations, 101 of which are known to be associated with different disorders”, says the lead researcher.
It is currently difficult to determine the number of diseases that share this underlying mechanism, but it is known to even be related to cancer. “The chances of developing therapies aimed at this mechanism are much greater”, highlights the scientist from the German institute.
the spanish team
The head of the Laboratory of Molecular Biophysics at IRB Barcelona, ​​​​​​Xavier Salvatella, contributed to characterize the consequences of the mutation on the structural properties of the protein studied in this research.
Consulted by SINC, Salvatella says that this work explains that understanding “how intrinsically disordered proteins perform their functions allows, in turn, understanding the consequences of mutations and, therefore, the mechanisms of associated diseases”.
these proteins. in their sequence they show how these ‘directional labels’ work by telling them which condensate to go to
In Salvatella’s words: “The discovery, led by Dr. Hnisz and his team, to which Carla GarcÃa-Cabau and I had the pleasure of contributing, opens the door to new diagnoses that may lead to the elucidation of many other diseases, as well as possible future therapies.
On the possibility of applying these discoveries to medical practice, the also researcher at the Catalan Institute of Research and Advanced Studies (ICREA) clarifies that, although he understands that it is necessary to ask this question, “an answer would still be premature”, since What they discovered it is “the molecular mechanism of a disease that perhaps, in the long term, could facilitate the development of therapies”.
Reference:
Hnisz D., Mensah MA et al. “Aberrant phase separation and nucleolar dysfunction in rare genetic diseases“. Nature (2023).