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Can Proteomics Reveal Therapeutic Targets for Down Syndrome?

Written by | Published: 05.08.2013

In an attempt to locate biomarkers for treatment purposes, proteomics researchers, led by a team at the University of Toronto, compared the proteomic profiles of amniotic fluid cells from Down syndrome (DS) cases against the profile of amniocytes from fetuses with no DS. Since amniotic fluid surrounds the developing fetus, understanding the proteomic changes in the presence of DS may provide insight into genotype-phenotype associations and aid in discovery of targets for future therapeutics.1

A relatively high incidence syndrome, DS affects one in 750 births in the United States. It is caused by an extra copy of chromosome 21 and characterized by congenital defects, cognitive impairment, and increased risk of cardiovascular disease, leukemia, and Alzheimer’s disease. While maternal blood tests using several biomarker proteins can point to a DS diagnosis, they are only 60% accurate with 5% false positives. The alternate amniocentesis in which amniotic fluid is withdrawn is more invasive and can slightly increase the chances of miscarriage.2 Estimates suggest that 92% of parents with fetuses diagnosed with DS terminate the pregnancy.3

Carrying on from earlier research in 2010, the Toronto team used stable isotope labeling with amino acids in cell culture (SILAC) and tandem mass spectrometry (MS/MS) to identify significant differences in protein levels between DS and non-DS amniotic fluid. When the outcome was adjusted to delete false positives, they found 60 proteins that were either significantly decreased or increased in the DS population. From this list of high probability proteins, the team performed selective reaction monitoring (SRM) to reduce the initial list down to nine. Of the nine, two proteins showed consistent and significant differential expression: superoxide dismutase 1 (SOD1) and neural export signal (NES).1

In the DS amniotic cells, SOD1 was consistently overexpressed. Regulated by the SOD1 gene located on chromosome 21, this protein is involved in free radical clearing and has been associated with two types of neurodegenerative disease. The first is amylotrophic lateral sclerosis type 1 (ALS), which affects the motor neurons. In the second, SOD1 forms toxic fibrillar aggregates that lead to neurodegeneration. The overexpression of SOD1 is an excellent example of how gene dosage contributes to protein manufacture. In DS, researchers might expect to find increased production of proteins coded for in genes located on chromosome 21 due to the extra copy.1

By contrast, the team found that NES was consistently and significantly underexpressed in the DS amniocytes compared with normal cells. Other studies have shown that NES expression is associated with central nervous system and neural tube stem cells and potentially plays an important role in central nervous system growth.1

One of the chief features of DS is cognitive impairment, and either one or both of NES and SOD1 may become targets for future interventions aimed at curing DS or at improving cognitive function in people with DS. However, the authors note that because amniotic cells are nonhomogenous, containing stem cells and terminally differentiated cells, speculating on the function of proteins in the amniotic proteome should be approached with caution. The variability between individual fetuses with DS will also lead to potential misinterpretation. This experiment drew cell samples from three different DS fetal sacks and compared them with cell samples from five different controls, so this should minimize variability, but larger samples would be better.1

Keeping these cautions in mind, it is nevertheless exciting to think that there may well be targets for therapy in DS in the future. Since almost all DS fetuses are aborted (92%), a cure or even partial cure would certainly improve the odds for those diagnosed in the womb.


References

1. Cho, C.K., et al. (2013) ‘Quantitative proteomic analysis of amniocytes reveals potentially dysregulated molecular networks in down syndrome‘, Clinical Proteomics, 10 (1), 2

2. Canick, J.A., and Kellner, L.H. (1999) ‘First trimester screening for aneuploidy: serum biochemical markers‘, Seminars in Perinatology, 23 (5), (pp. 359–368)

3. http://www.bbc.co.uk/blogs/theeditors/2008/12/changing_attitudes.html

Comments

  1. Nicholas Sammons says

    SOD1 and NES are in utero drug targets for treating DS? This raises a lot of interesting moral/ethical questions.

    Reply

    • Heather Drugge says

      Hi Nicholas,

      I was surprised to learn that 92% of people who learn they are carrying a baby with DS terminate the pregnancy. If those people knew there was a cure, at least they might not terminate. NES and SOD1 are potential targets, but a lot more work will be necessary. But the whole idea of whether or not DS should be viewed as a disease is another question…

      Reply

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