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TRISOMY 21: The Future of Research Opens New Paths

Actualizado: 29 dic 2020


Down syndrome, also known as trisomy 21, is one of the most common genetic disorders. Researchers recently looked at proteins from people with trisomy 21 for the first time - the goal was to improve our understanding of how a supernumerary copy of chromosome 21 might affect human development. Research shows that trisomy 21, far from affecting only the proteins encoded by genes on chromosome 21, also affects proteins encoded by genes located on the other chromosomes.

Down syndrome, also known as trisomy 21, is one of the most common genetic disorders. Researchers from the University of Geneva (UNIGE) and ETH Zurich (ETHZ), Switzerland, recently analyzed proteins from individuals with trisomy 21 for the first time: the goal was to improve our understanding of how a supernumerary copy of chromosome 21 might affect human development. Published in the journal Nature Communications, the research shows that trisomy 21, far from affecting only proteins encoded by genes on chromosome 21, also impacts proteins encoded by genes located on the other chromosomes. In fact, cells are overwhelmed by the excess protein generated by tripled genes and cannot regulate the amount of protein. These results provide a new insight into Down syndrome and its symptoms based on the study of proteins, revealing the different results of an excess of chromosome 21 in cellular behavior.

Symptoms of Down syndrome, or trisomy 21, the most common genetic disease, include facial dysmorphism, intellectual disability, poor muscle tone, and congenital heart disease. The syndrome is the result of the presence of three chromosomes 21, which explains why research so far has focused on analyzing DNA and the transcriptome (all messenger RNAs synthesized from the genes of our genome). "However," explains Stylianos E. Antonarakis, honorary professor at the UNIGE Faculty of Medicine, "proteins are highly informative molecules, as they are more closely linked to the clinical signs of the syndrome.

Studying them allows for new hypotheses about Cellular mechanisms altered by trisomy 21. "However, analyzing all the proteins in clinical samples is technically a very difficult task, which is why the UNIGE researchers joined forces with a team led by Professor Ruedi Aebersold of ETHZ, who is a world expert in proteome studies.

Scientists were able to quantify 4,000 of the 10,000 proteins synthesized by skin cells, a world premiere, using SWATH-MS, a new mass spectrometry technique developed by ETHZ.

The protein differences between Down syndrome cells and a person without the genetic abnormality are low (1.5 times higher for the proteins produced by genes on chromosome 21). They are difficult to detect with traditional techniques, which means that it has been necessary to wait for an ultrasensitive method to be developed to detect small variations. "Furthermore, the goal was only to analyze protein variations due to the genetic abnormality, and not variations that can be attributed to individual differences. Therefore, we worked on fibroblast cells from a pair of twins that shared the same genetic background." . except that one has trisomy 21 and the other does not ", adds Christelle Borel, a researcher at the Department of Genetics and Development of the UNIGE School of Medicine.

Cellular mechanism of poor self-regulation discovered

Un examen detallado de las muestras de gemelos reveló varios hallazgos importantes para mejorar nuestra comprensión del impacto del síndrome de Down en las células. Se observaron variaciones cuantitativas significativas en las proteínas que no están codificadas exclusivamente de genes en el cromosoma 21, sino también de genes que se asignan a otros cromosomas. La trisomía 21 provoca una sobredosis de ARNm y proteínas que desregulan las funciones celulares del individuo afectado. Luego, los investigadores observaron un mecanismo celular para la producción de proteínas autorreguladas, que era capaz de contrarrestar una sobreabundancia inusual de proteínas. En condiciones normales, este mecanismo ayuda a corregir excesos menores y regula la cantidad de proteína que necesitan nuestras células. Pero, debido a un cromosoma 21 adicional, que en sí mismo codifica proteínas, las células quedan con un exceso de proteínas y el mecanismo de autorregulación ya no puede controlar y restringir la cantidad. "Por primera vez", dice el profesor Antonarakis, "tenemos un análisis exhaustivo de las proteínas desreguladas por la trisomía 21, lo que puede explicar las causas de los diferentes síntomas del síndrome de Down".

UNIGE geneticists also found that trisomy 21 also affected the various substructures of the cell, especially the mitochondria, which are responsible for the energy processes of the cell. But here the problem is the opposite: the proteins that make up the mitochondria are excessively diminished and affect their proper functioning. The latest result was validated with samples from other trisomy 21 patients: it showed that the type of proteins affected is also extremely important in understanding what causes the symptoms. "Generally speaking, protein turnover is accelerated in trisomic cells. Then there are two types of proteins," says Christelle Borel. "The first is assembled as a complex to perform a precise function. The second, on the other hand, operates alone. We found that it is the proteins in the complexes that degrade the most rapidly in trisomic cells, which is something that had not been discovered. before ". In fact, the proteins that are assembled naturally regulate each other by forming complexes, which means that their excess is controlled. On the contrary, there is an excess of solitary proteins that are not eliminated by the cell because they are functional on their own.

New perspectives for research in medical genetics.

The geneticists at UNIGE, in collaboration with the experts at ETHZ, have taken a major step forward in our understanding of trisomy 21 by going beyond the gene and transcriptome to reach proteins. These initial discoveries, together with the demonstration of technical feasibility, open up new perspectives for research, as the methodology can be applied to other genetic diseases. "Now we have to find which of the dysregulated proteins are responsible for each particular symptom of Down syndrome. Then we have to see if new discoveries are possible for other cell types, such as neurons or heart cells, severely affected by trisomy. twenty-one". Professor Antonarakis concludes. Source

Materials provided by the Université de Genève. Journal reference: Yansheng Liu, Christelle Borel, Li Li, Torsten Müller, Evan G. Williams, Pierre-Luc Germain, Marija Buljan, Tatjana Sajic, Paul J. Boersema, Wenguang Shao, Marco Faini, Giuseppe Testa, Andreas Beyer, Stylianos E. Antonarakis, Ruedi Aebersold. Systematic profiles of proteome and proteostasis in human trisomy 21 fibroblast cells. Nature Communications, 2017; 8 (1) DOI: 10.1038 / s41467-017-01422-6

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