• Down syndrome is one of the most common genetic abnormalities in humans
  • So far there has been no cure for this disorder
  • The OLIG1 and OLIG2 genes are responsible for the neuronal development during embryogenesis
  • This discovery will lead to new gene targeted therapy, which will improve the life quality of patients with DS

Introduction – Down syndrome (DS) is a genetic disorder caused by the presence of the third copy of the 21st chromosome, also known as trisomy 21 (1). This disorder is associated with delays in physical growth as well as mental development. These patients usually present with intellectual disability and characteristic facial features.

Fig.1 shows the characteristic facial features in people with DS.
Image adapted form Google.

The human karyotype holds 46 chromosomes (23 chromosomes from each parent) plus the sex chromosomes (either XX or XY). In the case of Down Syndrome, the patient has one extra chromosome copy. This extra copy is thought to occur by chance(2) . In this case the karyotype is 46XX +21 for females, and 46XY+21 for males.

Fig.2 presents the human karyotype in patients with the extra 21st chromosome.
Image adapted from (3) .

The extra genetic material in DS results in overexpression of the 310 genes located on the 21st chromosome. Down syndrome can be identified during pregnancy by prenatal screening followed by diagnostic testing or after birth by direct observation and genetic testing. The diagnosis can be made before birth with different invasive methods such as amniocentesis or chorionic villus sampling (3) . There is no cure for this disorder, but scientists are developing new treatments to increase the quality of life for these patients.

Statistics – Down Syndrome is one of the most common genetic disorders in humans. It occurs in about one per 1000 babies born each year. (4) 

Latest research – All the characteristics associated with this disorder come from the overexpression of the genes in the 21 chromosomes. Scientists have discovered that the genes responsible for neuronal growth deficiency in DS are OLIG1 and OLIG2(5) . The Oligodentrocyte Transcrition Factor is the protein encoded from these genes. This protein is restricted to the central nervous system (6) . Its job s to differentiate motor neurons from oligodentrocytes (types of cells in the brain matter). It does so by sustaining replication in the early development of the fetus (7) .

Fig.3, presents the role these genes have in neuronal development. The differences in myelin basic protein (Mbp) (A,C,E,G) or proteolipid protein (Plp) show the importance that these genes have in vitality of neuronal progress.
Image adapted from (5) .

During embryogenesis the OLIG1 and OLIG2 promotes neuronal differentiation in the pluripotent cells, then OLIG2 switches to oligodentrocyte promotion. The phosphorylated state of this protein determines the fate of cortical progenitor cells, meaning the progenitor cell will either become a supportive cell such as astrocytes, or it will remain as a neural precursor (8) . With overexpression of these genes from the extra copy the balance between the excitatory and inhibitory neurons in the brain is disrupted, and it is believed that this is the reason for the mental retardation in patients with DS. With the discovery of these genes, responsible for such a big role in the neuronal development, researchers can now focus the treatment to these specific genes and have much efficient outcomes (9) . Using the stem cells with the extra 21st chromosome, scientists were able to create a 3D brain organiod and brain mouse models, which they implanted into the brain of the mice a day after the mice had been born. This led to them to find that inhibitory neurons — which make your brain function smoothly — were overproduced in both models, and adult mice had impaired memory (10).

Conclusion – With all of this in mind we can infer that this research will open new doors for DS therapy. The patients who live with this disorder will have a chance to better the quality of their lives. These studies will lead the way for new drugs to be developed targeting these specific genes.As such this might reverse the abnormal brain development and improve the cognitive function after birth.

COPYRIGHT: This article is the property of We Speak Science, a non-profit institution co-founded by Dr. Detina Zalli and Dr. Argita Zalli. The article is written by  Arrita Beqa, University of Prishtina, Kosovo.

References:

  1. Patterson, D (Jul 2009). “Molecular genetic analysis of Down syndrome”. Human Genetics126 (1): 195–214. doi:10.1007/s00439-009-0696-8PMID 19526251.
  2. “What causes Down syndrome?”. 2014-01-17. Archivedfrom the original on 5 January 2016. Retrieved 6 January 2016.
  3. “How do health care providers diagnose Down syndrome?”Eunice Kennedy Shriver National Institute of Child Health and Human Development. 2014-01-17. Archivedfrom the original on 7 March 2016. Retrieved 4 March 2016.
  4.  Weijerman, ME; de Winter, JP (Dec 2010). “Clinical practice. The care of children with Down syndrome”. European Journal of Pediatrics. 169 (12): 1445–52. doi:10.1007/s00431-010-1253-0PMC 2962780PMID 20632187.
  5. https://www.nature.com/articles/nn.2600
  6.  “OLI G2”. Atlas of Genetics and Cytogenetics in Oncology and Hematology.
  7. Setoguchi T, Kondo T (Sep 2004). “Nuclear export of OLIG2 in neural stem cells is essential for ciliary neurotrophic factor-induced astrocyte differentiation”The Journal of Cell Biology166 (7): 963–8. doi:10.1083/jcb.200404104PMC 2172021PMID 15452140.
  8.  Sun Y, Meijer DH, Alberta JA, Mehta S, Kane MF, Tien AC, Fu H, Petryniak MA, Potter GB, Liu Z, Powers JF, Runquist IS, Rowitch DH, Stiles CD (Mar 2011). “Phosphorylation state of Olig2 regulates proliferation of neural progenitors”. Neuron. 69 (5): 906–17. doi:10.1016/j.neuron.2011.02.005PMC 3065213PMID 21382551.
  9. https://www.sciencedaily.com/releases/2019/05/190523142958.htm
  10. Ranjie Xu, Andrew T. Brawner, Shenglan Li, Jing-Jing Liu, Hyosung Kim, Haipeng Xue, Zhiping P. Pang, Woo-Yang Kim, Ronald P. Hart, Ying Liu, Peng Jiang. OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down SyndromeCell Stem Cell, 2019; DOI: 10.1016/j.stem.2019.04.014