BioISI researcher proposes in the journal Science a new perspective on protein regulation in neurodegenerative diseases

An article published in the latest issue of the journal Science proposes a new conceptual model for understanding how the body controls and protects proteins outside of cells, with relevance to research on neurodegenerative diseases such as Alzheimer's, Parkinson's, or paramyloidosis, which is also known in Portugal as "disease of the little feet."

The article is authored by Cláudio M. Gomes, professor at the Faculty of Sciences of the University of Lisbon (Ciências ULisboa) and researcher at the Institute of Biosystems and Integrative Sciences (BioISI), and Michele Vendruscolo, professor at the University of Cambridge.

In the article “Systems-level organization of extracellular proteostasis”, the two researchers review and reorganize scientific knowledge about extracellular proteostasis, that is, the set of mechanisms that helps maintain the balance and integrity of proteins in the extracellular environment.

"Based on available knowledge about protein homeostasis, the authors propose that extracellular proteostasis be understood as a hierarchical system organized into three levels—pericellular, tissue, and systemic—that extends from the cell surface and immediate microenvironment to biological fluids and organs involved in the clearance and elimination of proteins," says an explanatory note about this work, developed within the framework of the European project TWIN2PIPSA.

The article emphasizes that the extracellular environment is not a passive space, but rather an active protective system against the harmful effects generated by the accumulation, alteration, or aggregation of proteins.

"In this context, different components — from proteins that stabilize or eliminate damaged proteins to vesicles, receptors, immune cells, and transport and clearance pathways — work in a coordinated manner to maintain protein balance in the extracellular environment," the same note also states.

In recent years, the laboratory coordinated by Cláudio M. Gomes at BioISI has been developing research on protein aggregation, molecular chaperones, and neurodegeneration, including extracellular control and defense mechanisms. In this context, the new article also helps to frame this work within a broader and more integrated model.

“Given that several aspects of this architecture remain to be defined, this proposal could influence new research questions, how experiments are designed, and how results are interpreted,” emphasizes Cláudio M. Gomes. “There was already a lot of relevant knowledge about the mechanisms that control and protect proteins outside cells, but an integrated view that organized them as parts of the same system was lacking,” adds the BioISI scientist.

Protein balance is essential for health. When this balance fails, it increases the risk of accumulation of altered proteins and associated pathologies, including neurodegenerative diseases and systemic amyloidosis. "In these pathologies, the accumulation of altered proteins outside the cells contributes to tissue damage and disease progression. This new study shows that this pathological process may result, in part, from the failure of the mechanisms that normally control, neutralize, and eliminate these proteins in the extracellular environment," the researchers state.

Although it is a conceptual article, the authors believe that the model now published can help guide future research with biomedical and therapeutic potential, namely through the development of "therapeutic strategies focused on stabilizing extracellular proteins, enhancing clearance pathways, and modulating fluid transport."

“The next step is not to move directly to therapy, but to use this framework to better guide experimental research and test new hypotheses arising from the proposed model,” says Cláudio M. Gomes. At BioISI, we are well-positioned for this because we address these problems at multiple biological scales, within the context of the unit's three research programmes, which range from biomolecules to cellular networks and broader biological systems. In this sense, the future is promising: the model now proposed opens up several lines of research for the coming years and helps us to formulate more integrated and ambitious experimental questions,” concludes the researcher.