Researchers have identified a promising strategy to improve memory and brain cell function in models of 22q11.2 Deletion Syndrome.
The study, first published as a Reviewed Preprint in eLife and appearing today as the final version, shows that reducing the levels of the protein EMC10 can restore both cellular and cognitive function in mouse and human cell models of 22q11.2 Deletion Syndrome. The editors describe this as an important study, backed by compelling evidence supporting EMC10 reduction as a promising therapeutic strategy.
22q11.2 Deletion Syndrome, also known as DiGeorge syndrome, is a genetic condition present from birth, caused by a small missing section of genetic material on chromosome 22. It affects about 1 in 4,000 births and can lead to a wide range of symptoms, including learning delays, speech difficulties, attention deficit disorders and cleft palate. It is also one of the strongest known genetic risk factors for developing schizophrenia. People with the condition often require lifelong care to monitor and manage symptoms as they arise.
It has been established in mouse models that a group of molecules called microRNAs – which help control gene activity – are disrupted in 22q11.2 Deletion Syndrome. A key effect of this disruption is an increase in the activity of Emc10, a gene which produces the protein Emc10 that plays a role in the biogenesis of membrane proteins. By assisting in the production and assembly of these membrane proteins, Emc10 plays a crucial role in how cells function and interact with their environment. (Note: Emc10 refers to the mouse gene, while the capitalised EMC10 refers to the equivalent human gene. Similarly, Emc10 refers to the protein in mice, whereas EMC10 refers to the protein in humans). The authors have previously shown that reducing levels of Emc10 can reverse certain cognitive symptoms in a mouse model of 22q11.2 Deletion Syndrome.
“Despite its prevalence and serious impact, there are currently no targeted therapies that address the underlying molecular mechanisms of 22q11.2 Deletion Syndrome,” says lead author Martin Lackinger, an Associate Research Scientist at the Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, US. “We aimed to build on previous findings and test whether EMC10 levels are also increased in human cell models of the condition, and whether reducing EMC10 activity could alleviate the symptoms.”
To test this, the team first created neurons from stem cells taken from people with and without 22q11.2 Deletion Syndrome. Using two methods, one mimicking natural development and one using a gene called NGN2 to rapidly create neurons, they found that brain cells with a 22q11.2 deletion had reduced levels of certain microRNAs, including miR-185, which plays a role in brain development. As expected, this drop in microRNA activity also led to abnormally high levels of EMC10.
Mouse models of 22q11.2 Deletion Syndrome show impaired formation of brain dendrites – the short, branched extension of a nerve cell which receives signals from other neurons – a problem that is partially reversed by reduction of Emc10 levels. To test whether the same occurs in human neurons, the researchers used genetic editing tools to reduce EMC10 levels in the 22q11.2 deletion neurons. In untreated neurons from people with 22q11.2 Deletion Syndrome, dendrites were shorter, fewer and less complex. But when EMC10 was reduced, dendritic growth returned to normal levels. Interestingly, neurons with complete EMC10 removal showed even more branching than control neurons, suggesting a strong restorative effect.
The team also measured how well the neurons could signal using calcium—a key messenger in the brain. In the 22q11.2 deletion cells with high EMC10, calcium signalling was weak. But after reducing EMC10, the cells’ calcium response was restored to normal.
Seeking to understand the broader impact of EMC10, the researchers used transcriptomic profiling to look at which genes were turned on or off. Reducing EMC10 restored the activity of hundreds of genes, including those involved in brain development, synapse formation, and cell signalling. Several of the corrected genes – such as RBFOX1, RGS4, and PCDHA2 – are already known to be associated with schizophrenia risk, potentially explaining the psychiatric symptoms seen in 22q11.2 Deletion Syndrome.
To test whether these cellular findings could translate into a real-world treatment, the team next focused on adult mouse models. They aimed to determine whether high EMC10 levels might cause ongoing problems in the mature brain, or if it causes an irreversible impact on brain maturation during early development.
To this end, they lowered Emc10 levels in adult mice with a 22q11.2 deletion and compared how well they performed on tests of social memory. This is a core cognitive skill that involves recognising others and recalling past social experiences – functions that are often impaired in schizophrenia and 22q11.2 Deletion Syndrome. The treated mice performed significantly better than untreated mice, and their activity levels, anxiety and general behaviour remained unchanged. This shows that restoring Emc10 levels in adult mice with 22q11.2 deletions can significantly improve cognitive deficits, highlighting a broad window for therapeutic intervention and establishing Emc10 as a promising target for postnatal interventions.
To explore a potential treatment strategy, the researchers created antisense oligonucleotides (ASOs) – short strands of synthetic genetic material designed to block Emc10’s communication with other neurons. These ASOs were administered to the fluid surrounding the brain of adult mice at eight weeks old (the cerebrospinal fluid) and successfully reduced Emc10 levels in key regions such as the hippocampus and prefrontal cortex. The team also found that they improved both social and spatial memory. A second ASO, targeting a different region of the Emc10 gene, produced the same effects, confirming this result. Importantly, the benefits lasted with both ASOs. Mice showed improved memory for more than two months after a single ASO treatment. Emc10 levels remained low in multiple brain areas at the nine-week mark. This suggests that the effects of treatment are long-lasting and potentially manageable with infrequent dosing.
“Our findings show strong preclinical evidence that therapies reducing EMC10 levels may be a way to reverse some of the core cognitive symptoms seen in 22q11.2 Deletion Syndrome,” says senior author Joseph Gogos, Principal Investigator at the Mortimer B. Zuckerman Mind Brain and Behavior Institute, and co-director of the Stavros Niarchos Foundation (SNF) Center for Precision Psychiatry and Mental Health, Columbia University. “What’s especially promising is that the improvements we’ve seen in mice can happen in adulthood, and that they last, emphasising a broad temporal window for therapeutic and preventive intervention in 22q11.2 deletion-associated cognitive and behavioural symptoms. Future studies will need to explore long-term safety, optimal dosing, and how EMC10-targeting treatments interact with other features of the disorder before the treatment can potentially be brought to the clinic.”
Media contacts
Emily Packer
eLife
e.packer@elifesciences.org
+441223855373George Litchfield
eLife
g.litchfield@elifesciences.org
About
eLife transforms research communication to create a future where a diverse, global community of scientists and researchers produces open and trusted results for the benefit of all. Independent, not-for-profit and supported by funders, we improve the way science is practised and shared. In support of our goal, we introduced the eLife Model that ends the accept–reject decision after peer review. Instead, papers invited for review are published as Reviewed Preprints that contain public peer reviews and an eLife Assessment. We also continue to publish research that was accepted after peer review as part of our traditional process. eLife is supported by the Howard Hughes Medical Institute, Knut and Alice Wallenberg Foundation, the Max Planck Society and Wellcome. Learn more at https://elifesciences.org/about.
To read the latest Neuroscience research in eLife, visit https://elifesciences.org/subjects/neuroscience.
