The discovery of targetable genes on ‘chromosome 21’ could lead to potential therapies for Down syndrome and Alzheimer’s-related conditions.
A recent landmark discovery demonstrates how three specific master regulator genes (BACH1, PKNOX1, and GABPA) on chromosome 21 drive brain changes in Down syndrome.
The findings reveal that an extra copy of the chromosome 21 (trisomy 21) disrupts the brain’s genetic activity, leading to the intellectual disabilities that impair learning and memory.(1✔ ✔Trusted Source
Single-cell atlas of the developing Down syndrome brain cortex
Go to source
)
The breakthrough in Down syndrome brain development was uncovered by researchers from Duke-NUS Medical School and Imperial College London and published in Nature Medicine.
The study offers new prospects for treating both Down syndrome and Alzheimer’s-related brain conditions.
Is Down Syndrome Brain Function Biologically Adjustable?
The researchers found that these three genes are overactive in human brain cells derived from individuals with Down Syndrome, disrupting the normal activity of hundreds of other genes involved in learning and memory. Together, these widespread changes may help explain how an extra chromosome reshapes brain function.
To explore whether these effects could be modulated, the team used a modern molecular approach known as antisense oligonucleotides or ASOs: short, synthetic strands of genetic material designed to precisely reduce the activity of specific genes.
When the researchers “turned down” the activity of the three overactive genes in laboratory-grown human brain cells, they observed a partial restoration of more typical gene activity patterns.
While this work is early-stage and conducted entirely in the lab, it provides proof of concept that some of the molecular changes associated with Down Syndrome may be biologically adjustable, offering a new framework for understanding the condition.
Can Advanced Molecular Modelling Reveal Insights Into Down Syndrome?
Dr. Michael Lattke, Department of Brain Sciences, Faculty of Medicine at Imperial College London and first author of the study, said:
“Our study shows how combining advanced technologies for analysing, modelling and modulating gene activity can reveal new biological insights into complex conditions. By identifying key genetic regulators and demonstrating that their activity can be adjusted in human brain cells, we provide a foundation for future research into Down syndrome.”
Down syndrome is also the most common genetic cause of Alzheimer’s disease, and individuals with Down syndrome have a much higher lifetime risk of developing Alzheimer’s-related brain changes.
By clarifying how chromosome 21 disrupts gene regulation in brain cells, the findings may help inform future studies into shared biological pathways between these conditions, though the researchers stress that clinical applications remain a long-term goal.
Cellular-Level Research Reveal the Root Causes of Neurological Changes
Professor Vincenzo De Paola, is from the Neuroscience & Behavioural Disorders Signature Research Programme at Duke-NUS.
The senior author of the study, who is also Honorary Professor in the Department of Brain Sciences, Faculty of Medicine at Imperial College London, said:
“This discovery would have been impossible without the families who contributed to this research, and we are profoundly grateful for their generosity. By analysing individual cells at unprecedented scale and depth, we uncovered previously unresolved molecular mechanisms and moved closer to understanding the root causes of Down syndrome’s neurological features.”
“Benchmarking current in vitro and humanised in vivo models against primary fetal tissue allowed us to define a practical roadmap to help the field choose the most appropriate experimental systems to study specific aspects of the condition.”
Professor Lok Sheemei, Duke-NUS’ Interim Vice-Dean for Research, said:
“This study exemplifies how fundamental research can illuminate the biological mechanisms behind complex conditions. The result is more than a dataset. It is a new framework for understanding how Down syndrome unfolds at the cellular level.”
“The atlas pinpoints specific genes, pathways, and cell populations that may drive neurological changes, offering potential targets for future therapies.”
Reference:
- Single-cell atlas of the developing Down syndrome brain cortex – (https://www.nature.com/articles/s41591-026-04211-1)
Source-Eurekalert