Protein analysis provides new insights into Down syndrome

Friday, 01 December, 2017

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European researchers have analysed the proteins of individuals with trisomy 21 — more commonly known as Down syndrome — for the first time. Published in the journal Nature Communications, the results provide new insight into Down syndrome and its symptoms, revealing the different outcomes of an excess of chromosome 21 on cell behaviour.

Down syndrome is the world’s most common genetic disease, with symptoms including facial dysmorphism, intellectual impairment, poor muscular tone and congenital heart disease. The syndrome results from the presence of three chromosomes 21, which is why research until now has focused on analysing DNA and transcriptome (all the messenger RNAs synthesised from genes of our genome).

“Nevertheless, the proteins are highly informative molecules since they are more closely linked to the clinical signs of the syndrome,” said Stylianos E Antonarakis, an honorary professor at the University of Geneva (UNIGE). “Studying them makes it possible to posit new hypotheses about the cellular mechanisms disturbed by trisomy 21.”

Analysing all the proteins from clinical samples is technically a very difficult task — which is why the UNIGE researchers joined forces with a team led by Professor Ruedi Aebersold from ETH Zurich (ETHZ), a world expert in proteome studies. Together, the scientists succeeded in quantifying 4000 out of the 10,000 proteins synthesised by skin cells using SWATH-MS, a mass spectrometry technique developed by ETHZ.

The protein differences between the cells of Down syndrome and a person without the genetic anomaly are low (1.5 times higher for the proteins produced by the chromosome 21 genes) and thus difficult to detect with traditional techniques, meaning it was necessary to wait for an ultrasensitive method to be developed in order to detect the tiny variations.

“What’s more, the aim was only to analyse the protein variations due to the genetic anomaly, and not the variations that can be attributed to individual differences,” said UNIGE researcher Christelle Borel. “So we worked on fibroblastic cells from a pair of female twins who shared the same genetic background, except that one has trisomy 21 and the other doesn’t.”

Detailed examination of the twin’s samples revealed several major findings. Significant quantitative variations were observed in the proteins that were not encoded exclusively from genes on chromosome 21 but also from genes that map to other chromosomes. Trisomy 21 causes an overdose of mRNA and proteins that dysregulate the cellular functions of the affected individual.

The researchers then observed a cellular mechanism for self-regulating protein production, which was capable of counteracting an unusual overabundance of proteins. Under normal conditions, this mechanism helps correct minor excesses and regulates the amount of protein needed by our cells. But because of an extra chromosome 21, which itself encodes proteins, the cells are left with a surplus of proteins and the self-regulating mechanism is no longer able to control and restrict the quantity.

“For the first time, we have a comprehensive analysis of the proteins deregulated by trisomy 21, which may explain the causes of the different symptoms of Down syndrome,” said Professor Antonarakis.

The geneticists also found that trisomy 21 also affected the cell’s various substructures, especially the mitochondria, which are responsible for the cell’s energy processes. Here, the proteins that make up the mitochondria were found to be excessively diminished, which affected their correct functioning. This result was validated with samples from other patients with trisomy 21, showing that the type of proteins affected is also extremely important for understanding what causes the symptoms.

“In general terms, protein turnover is accelerated in the trisomic cells,” said Borel. “Then there are two kinds of proteins. The first assemble as a complex to perform a precise function. The second, on the other hand, operate alone. We discovered that it is the proteins in complexes that are degraded most quickly in the trisomic cells, which is something that could not have been discovered before.”

In fact, the proteins that assemble regulate mutually and naturally by forming the complexes, meaning their surplus is controlled. By contrast, there is an excess of solitary proteins that are not eliminated by the cell because they are functional alone.

The researchers have thus 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 the technical feasibility, open new perspectives for research, since the methodology can be applied to other genetic diseases.

“We now need to find which of the deregulated proteins are responsible for each particular symptom of Down syndrome,” said Professor Antonarakis. “Then we need to see if new discoveries are possible for other types of cells such as neurons or heart cells, severely affected by trisomy 21.”

Image credit: © Hofmann

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