R & D encourages protein aggregation in neurodegenerative diseases

New research reveals that RNAs, which are crucial for cells to produce proteins, are also involved in protein aggregation, where proteins do not bend correctly and "aggregate" together in aggregates. If the cells can not eliminate them, they become toxic and prevent the cells from functioning properly. This discovery, conducted by scientists from the Center for Genomic Regulation (CRG) in Barcelona, ​​reveals that RNAs act as a "scaffold" to contain different proteins adhering to RNA together and that some RNA molecules with distinct properties they attract more protein and encourage proteins to be aggregated. They also studied how an RNA called FMR1 is implicated in a neurodegenerative disease called Fragile X tremor syndrome, or FXTAS.

Many neurodegenerative diseases are linked to protein aggregation, including amyotrophic lateral sclerosis and Alzheimer's disease. We know that proteins can form toxic aggregates, but until now, the contribution of nucleic acid molecules such as RNA has been questioned.

CRG researcher and ICREA researcher Gian Gaetano Tartaglia and CRG Alumni Teresa Botta-Orfila, and currently at the Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), wanted to understand how RNA can promote 39; aggregation. In their research, published in the journal Reports on cellsthey found that specific RNAs interact with many proteins within cells and that these RNAs have distinct properties – they are structured, have a long area of ​​untranslated genetic code called UTR region and often contain different repetitions of genetic code ( called CGG Expansions) within them.

"Using theoretical tools, Fernando Cid in the group studied how an RNA called FMR1 attracts proteins in FXTAS," explains Gian Gaetano Tartaglia. "Together with Teresa we then processed the proteins that bind to the FMR1 using new laboratory approaches and identified one of them as a protein called TRA2A, using cells, mouse models of FXTAS and postmortem samples from patients, we have confirmed that TRA2A aggregates with FMR1 in this disease and we have studied the consequences of its aggregation.We now know the components of some of these aggregates, we can begin to understand what is causing this disease and could reveal new ways to treat it. "

Botta-Orfila continues: "We were surprised to find that our planned interactions could act as a biomarker for the disease and it was particularly exciting to detect the TRA2A protein in the brains of people with the disease – it was one of the most important discoveries in my time at CRG: A lot of things suddenly made sense.The TRA2A protein we discovered was involved in FXTAS involved in RNA splicing, a crucial process that ensures that the pieces of the genetic code are in the & # 39; correct order and produce the right protein As this protein aggregates into FXTAS, it is not performing the splicing process correctly and, as a result, many RNAs are altered and can not function properly. "

And the team's biomarker discovery has raised more interesting questions that they would like to answer. "Many of the genes we found were deregulated due to protein aggregation related to brain development, which is a key factor in the development of the disease," explains Gian Gaetano Tartaglia.

The team now has an arsenal of proteins to be tested for FXTAS and would like to extend its work to other complex diseases. In the long run, they would also like to discover the function of sticky RNAs. Together, this work could improve our understanding of complex diseases in which protein aggregation is important and could eventually reveal new ways to treat them.

This article has been republished from the materials provided by the Center for Genomic Regulation. Note: the material may have been modified for length and content. For more information, please contact the cited source.

Reference: Cid-Samper et al. 2019. An integrative study of protein RNA condensates identifies scaffold RNAs and reveals players in the fragile X-associated tremor / ataxia syndrome. Reports on cells. DOI: https: //doi.org/10.1016/j.celrep.2018.11.076.

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