Abnormal gene activity in Down syndrome affects lifelong brain development

The faulty activity of genes controlling the development of white matter in the brain may underlie cognitive symptoms of people with Down syndrome, according to a study in Neuron. Researchers analyzed gene expression in the brains of people with the disability, finding genes that control white matter development were affected from childhood through to adulthood. Current theory suggests intellectual disability in people with Down syndrome occurs due to changes before birth, so the researchers suggest their results could open up new possibilities for treatment.


Dr. Brian Skotko, Co-Director of the Down Syndrome Program, Massachusetts General Hospital (webpage):

Expertise: Board-certified medical geneticist with clinical expertise and translational research experience about Down syndrome

“This sweeping research demonstrates that Down syndrome is not just caused by extra genetic material from chromosome 21; but, instead, this extra chromosome has complex interactions with each and every other chromosome, which changes over time and in different regions of the brain. This research adds to a small number of recent papers which have also confirmed this. This means that potential treatments and future therapies for people with Down syndrome might need to look beyond chromosome 21 for some answers.

“When they drilled down to the nitty-gritty differences, these scientists discovered that one of the significant neurological differences is that the genetic changes in people with Down syndrome lead to less protective sheathing–called myelin–in their neurons. This finding likely offers an explanation, in part, for some of the intellectual disabilities associated with Down syndrome and a potential pathway for further treatment discovery.”

“Some members of the Down syndrome community might be concerned that some of the tissue samples used in this research originated from electively aborted fetuses with Down syndrome. According to the authors, these samples came from the NIH-funded Maryland Brain and Tissue Bank.”


Dr. Anita Bhattacharyya, Senior Scientist, Waisman Center, University of Wisconsin-Madison (webpage):

Expertise: How the development of the cerebral cortex is altered in developmental disorders characterized by mental impairment, focussing on Down syndrome and Fragile X syndrome.

“The study by Olmos-Serrano et al., is an elegant approach to define deficits in brain development in Down syndrome (DS). DS is caused by an extra chromosome 21 that contains more than 300 genes. Although DS is the most common genetic cause of intellectual disability and occurs frequently (about 1 in 700 births), the underlying missteps in brain development that lead to disability are not well understood.

“First, Olmos-Serrano et al. analyzed gene expression in post-mortem human brains to identify differences in the DS brain that may give clues to the causes of intellectual disability. Importantly, brains from different ages were analyzed – ranging from fetal to adult – to get an overall picture of brain development, rather than a snapshot in time.  The results showed that a major developmental pathway that was different in DS is the formation of myelin. Myelin is the insulator material that surrounds axons (the section of nerve cells that conduct electrical impulses in the brain) to enable better and faster signal conduction. That myelin is disrupted in DS is a novel finding, as most studies on DS focus on the neurons themselves, not the surrounding cells (oligodendrocytes). The results also highlight the value of studying human post-mortem samples, including fetal tissue, to understand human brain development. Future work could include sophisticated imaging studies to corroborate myelin defects in living individuals.

“The next step in the study was to move to a DS mouse model to better understand defects in myelination and test potential mechanisms. The authors showed that the DS mouse model had decreased myelination and this led to a decrease in signal conduction from neurons. The cross-species analyses and validation to link human pathology to mouse models of human disease is a compelling aspect of this study.

“These studies have identified myelination as a key neurodevelopmental deficit in DS and there will undoubtedly be calls for therapeutic intervention to help individuals with DS.  As the authors point out, strategies to enhance myelination may serve as therapeutic targets, but myelination is an extremely complex process that occurs over years in humans, so it may be some time before strategies are identified.”


Dr. Roger Reeves, Professor, Department of Physiology, Johns Hopkins University School of Medicine (webpage):

Expertise: Molecular genetic basis of Down syndrome; genomics.

“There are two kinds of thing that happen in Down syndrome. One is you have this extra copy of chromosome 21 and all the genes on that chromosome are expressed a little higher than they should be, which has an impact on all kinds of genes all over the whole genome. The second is that we consist of 100 trillion cells which talk to each other all the time, so if you start messing with those signals just a little bit from day one (because the chromosome 21 genes are over-expressed) you can have a cascade of events that really throw things off track.

“What the researchers have done here is really elegant: they have looked at gene expression in a number of different brain regions, and then looked at how that gene expression changes over time, comparing expression between people with a normal number of chromosomes and people with Down syndrome. This is an extremely rigorous analysis of the whole question of what genes are affected when you mis-express the genes on chromosome 21.

“The work gives us a really interesting picture of a specific set of genes that are mis-regulated in DS, and how that affects how neurons become insulated. That small disruption in turn affects how electrical signals are transmitted in the regions of the brain referred to as white matter. Speeding up or slowing down transmission even a little because the ‘wires’ are not as well insulated makes a huge difference. Just looking grossly at Down syndrome brains you can already see they are smaller, they have less surface area and there is less white matter. But seeing that genes for myelination were under-expressed and following that up with investigation at the cellular level really makes a convincing case.

“In considering the question of how this finding gives more hope for progress in research, my first thought was ‘we’re not going to have a pill tomorrow from this.’ But in fact it is exactly this kind of study which gives more hope than anything else, because it is elegant, solid basic research on which hundreds of other investigations can be based. This is an eminently well crafted piece of science which integrates genetic data with physical outcomes.”


Dr. Randall Roper, Associate Professor, Department of Biology, Indiana University-Purdue University Indianapolis (webpage): 

Expertise: Genetic and developmental bases of phenotypes related to Down syndrome.

This study shows that Down syndrome, which is caused by three copies of human chromosome 21, leads to both up and down regulation of more genes throughout the genome than are found on human chromosome 21.  It is quite a remarkable result, and this paper supports what has increasingly been noted by others.

“One of the most obvious characteristics of Down syndrome is the variability between individuals.  The results from this paper suggest that even with this variability, specific gene networks and developmental processes contributing to Down syndrome may be identified. This investigation may set the stage for therapies targeting altered gene expression for specific developmental processes. To better identify therapeutic targets, gene expression from more individuals than included in this study will need to be evaluated. Additionally, future studies will need to make important connections between gene dysregulation, effects on brain structure and neurobehavioral traits.

“This study also powerfully demonstrates that Down syndrome animal models used in a well-designed study provide additional and important information on the human condition. Results from the human gene expression studies led to novel findings about white matter in the animal model. The novel results from this paper strongly endorse that animal models are essential to further delineate cellular processes and mechanisms important in developmental disorders such as Down syndrome.”


Declared interests (see GENeS register of interests policy):

No interests declared.



Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination‘ by Olmos-Serrano et al, published in Neuron on Thursday 25 February, 2016.

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