Serious neurodegenerative diseases, such as Alzheimer's and ALS, are associated with toxic protein aggregates that prevent the proper functioning of brain cells. A new research highlights the role in this process of "accumulation" of harmful protein nucleic acid molecules such as RNA.

The study, conducted by the Department of Biology and Biotechnology Charles Darwin at Sapienza and the Center for Genetic Regulation of Barcelona, has discovered with theoretical models and laboratory experiments, the role of a specific RNA in a neurodegenerative disease called Fragile X Tremor Ataxia Syndrome, or FXTAS, characterized by intentional trembling and ataxia (uncoordinated movements). The results of the study were published in the Cell Reports journal.

RNAs, in addition to having a fundamental role for the cells that produce proteins, can be responsible for an abnormal protein aggregation that becomes toxic to the brain, if not eliminated by the cells. In particular, the researchers have observed that a specific RNA, called FMR1, holds together several proteins, like a sort of scaffolding and, attracting them in the same way as a magnet, it encourages their aggregation.

"We have understood which proteins are bound to the FMR1," explains Gian Gaetano Tartaglia, coordinator of the project, "and we have identified in the brain of people with the FXTAS disease one of these proteins, the TRA2A."

The latter is involved in RNA splicing, a fundamental process that ensures that the pieces of the genetic code are in the right order and can produce the right protein; since in the pathology examined TRA2A tends to aggregation, it does not perform a correct splicing process, causing the alteration of many RNA that can not function properly. The phenomenon is the critical factor in the development of brain disease.

"We were surprised to find that the interactions we envisaged," explains Teresa Botta-Orfila, the team's researcher, "could act as biomarkers of the disease: now that we know the components we can begin to trace the cause of the disease and this could lead to new approaches for the cure."

This work creates the foundation for innovative treatment methods. At the moment the team has a protein deposit to be tested for FXTAS and would like to extend its work into other complex diseases, recognizing the function of complicated RNA over the long term.

References:

An Integrative Study of Protein-RNA Condensates Identifies Scaffolding RNAs and Reveals Players in Fragile X-Associated Tremor/Ataxia Syndrome. Cid-Samper F, Gelabert-Baldrich M, Lang B, Lorenzo-Gotor N, Ponti RD, Severijnen LWFM, Bolognesi B, Gelpi E, Hukema RK, Botta-Orfila T, Tartaglia GG. Cell Rep. 2018 Dec 18;25(12):3422-3434.e7. 
DOI: 10.1016/j.celrep.2018.11.076.

Further Information

Gian Gaetano Tartaglia
Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome
giangaetano.tartaglia@uniroma1.it