By Charlene N. Rivera-Bonet | Waisman Science Writer
Three Waisman Center investigators and affiliates were awarded an internal grant to support Down syndrome research in its early stages. The funds were made possible through the Ann Dewey Down Syndrome Catalyst Fund at the Waisman Center.
The funded pilot projects will focus on better understanding different aspects of Down syndrome, including genetics, metabolism, and gut microbiome. “These grants will allow each lab to kickstart high-risk-high-reward research that are testing bold ideas about Down syndrome,” says Qiang Chang, PhD, director of the Waisman Center.
The grants were awarded to the labs of Xinyu Zhao, PhD, Jenni & Kyle Professor in Novel Neurodevelopmental Diseases, André Sousa, PhD, assistant professor of neuroscience, and Barbara Bendlin, PhD, professor of medicine in the School of Medicine and Public Health. “It’s an interdisciplinary breath of research that looks at Down syndrome from different perspectives, with the common goal of improving the lives of individuals with Down syndrome,” Chang says.
Duplicated genes
Down syndrome, also known as trisomy 21, is characterized by the triplication of the 21st chromosome, but how an extra copy of chromosome 21 genes can contribute to the different pathologies seen in Down syndrome is not fully known. Zhao’s funded pilot study will aim to identify genes in chromosome 21 whose duplication contributes to pathogenesis in Down syndrome such as neuronal stress, autophagy, and mitochondrial deficits.
Zhao will also explore the molecular pathways shared between Down syndrome and fragile X syndrome, the most common cause of inherited intellectual disability. Down syndrome and fragile X syndrome share many similarities such as a higher prevalence of autism spectrum disorder (ASD), deficits in expressive communication, seizure disorders, and mental health disorders. By directly comparing these two syndromes, Zhao hopes to unveil shared drug targets.
Altered metabolism
One defining feature of Down syndrome is intellectual disability, which includes deficits in cognition, attention, working memory, motor development and language. Previous research has found that individuals with Down syndrome have alterations in metabolism that may be caused by dysfunction of the mitochondria, which is important for proper brain development. Sousa’s proposed study aims to look into how changes in small molecules, such as lipids in brain cells affect brain development in Down syndrome.
Sousa will first characterize the metabolomic (small molecules) and the lipidomic (lipids in cell) differences between trisomy 21 and typical brain development using post mortem human brain tissue, as well as in organoids derived from induced pluripotent stem cells (iPSCs). This will allow Sousa and his lab to perform an integrative analysis to identify the molecular pathways that are disrupting biochemical and metabolic processes in Down syndrome.
Gut microbiome and aging
Individuals with Down syndrome appear to show signs of accelerated brain aging, and develop Alzheimer’s disease at increased rates. Research by Bendlin and colleagues has shown that the gut microbiome – or the collection of microbes such as bacteria, fungi, and viruses that naturally live in the gut – and intestinal health is altered in old age and Alzheimer’s disease. This, however, hasn’t been studied in Down syndrome.
Bendlin’s proposed pilot study will examine the composition and function of the gut microbiome in individuals with Down syndrome. After this characterization, the study will seek to understand the association between the gut microbiome and brain changes, blood plasma biomarkers of Alzheimer’s disease, and neurodegeneration in individuals with Down syndrome. As the gut microbiome may be a modifiable target, this pilot study may lead to therapeutic strategies to improve brain health and quality of life among these populations.
Zhao, Sousa, and Bendlin will receive a maximum one-year budget of $75,000, and may be eligible for a second year of support. The funding will allow researchers to obtain preliminary data, acquire samples, develop models and/or identify patient populations with the goal of enhancing the feasibility of future external funding to continue their projects.
“The knowledge acquired from these pilot projects will be a catalyst for future studies that will get us closer to interventions aimed at improving the health and quality of life of individuals with Down syndrome and other neurological conditions,” Chang says. “We are grateful to the Dewey family for supporting such important work.”
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