Completed Brain & Nervous System Genetics & Molecular Biology

Synaptic, Cellular and Neural Circuit Dysfunction in Down Syndrome

Funder Wellcome Charity-funded
Associated organisations Queen Mary University of London · The Francis Crick Institute · University College London Europe PMC affiliations are not treated as award recipients or mapped locations.
Funding £4.0M
Period Sept 2019 — Aug 2024

In plain English

AI plain-English summary

People with Down syndrome carry an extra copy of chromosome 21, and this extra genetic material disrupts how their brain cells communicate with each other. This matters because Down syndrome is a common genetic disorder that causes lifelong cognitive deficits and early-onset neurodegeneration, yet there are currently no therapies available. The researchers aim to pinpoint exactly which genes on the extra chromosome cause these neurological problems, which cells are affected, and how neural communication breaks down. They will use a unique set of mouse models carrying only parts of the extra chromosome, along with human neurons grown from stem cells of people with Down syndrome, to trace the problem from gene to protein to brain circuit. If successful, this work could identify specific proteins that drive cognitive impairment, opening the door to targeted drug treatments or gene-based therapies that reverse the deficits. While the research is fundamental science—understanding the basic mechanisms of how trisomy 21 harms the brain—it directly targets a condition with no current treatment, and the findings could eventually translate into life-changing therapies for people with Down syndrome.

View original technical description
Down syndrome (DS) is a common genetic disorder resulting from an extra copy of human chromosome 21 (Hsa21). This gene dosage disorder is characterised by cognitive deficits and early-onset neurodegeneration. It causes significant impact on the quality and longevity of life. Presently, there are no therapies. The key aim of our proposal is to establish the mechanisms by which trisomy 21 causes cognitive impairment in DS. By using a unique complement of segmental trisomy-containing mouse models and human DS induced pluripotent stem cell-derived neurons, together with cutting-edge genetics, biochemistry, imaging, electrophysiology, neural circuit tracing and systems neuroscience, we will identify the genes that cause neurological deficits in DS, define the cells that are affected, and discover the mechanisms that underlie dysfunctional neural communication. Identifying the responsible proteins and their roles in the brain will allow us to devise innovative pharmacological and gene-based therapeutic approaches to reverse the deleterious cognitive phenotypes. Our research strategy is based upon a significant bank of preliminary data. By using the diverse but complementary research skills within our collaborative group, we have the potential to deliver greater understanding of, and life-changing therapies for, people with DS.

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Researchers

Dean Nizetic (EPMC Awardee)Elizabeth Fisher (EPMC Awardee)John O'Keefe (EPMC Awardee)Trevor Graeme Smart (EPMC Awardee)Victor Tybulewicz (EPMC Awardee)

Related Research

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Original classification

Collaborative Award in Science

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