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Recent research from the University of Exeter Medical School has identified a correlation between gene isoforms expressed in the brain and the accumulation of the protein tau, a hallmark of Alzheimer's disease. Utilizing advanced long-read sequencing technology, this study provides new insights into gene expression and potential targets for dementia drug development.
Advanced Sequencing Techniques
The study, published in Nature Communications and funded by Alzheimer’s Research UK, the Medical Research Council, and the NIHR Exeter Biomedical Research Centre, employed cutting-edge long-read sequencing technology. This method can read longer and more complex sequences of genetic material in a single run than previously possible. The Exeter team combined this with newly developed data analysis tools to map the diversity of gene isoforms in the brains of mice engineered to carry a human mutant form of the tau protein.
Isoform Discovery and Implications
The research uncovered hundreds of new isoforms of genes implicated in Alzheimer's disease, with specific isoforms associated with tau accumulation. Notably, many isoforms identified in the mice were also differentially expressed in tissue samples from human donors who had died of Alzheimer’s. This cross-species validation underscores the relevance of the findings to human brain biology.
“Advances in technology are allowing us to map out molecular changes in the brain in greater detail than ever before,” said lead author Szi Kay Leung. “Through that we’re learning that the complex pathway of gene expression is key in the development of Alzheimer’s and could also hold the key to new treatments. We’ve made our analysis pipeline available as a resource to the community to stimulate further research in this area.”
Building on Previous Work
This study builds on previous work by the Exeter team, which identified thousands of new brain isoforms linked to various diseases. The current research delves deeper into the role of alternative splicing—a process generating different gene versions by combining various parts of the coding sequence. Understanding these mechanisms is crucial for developing therapeutic strategies targeting specific gene isoforms.
Future Directions
Jonathan Mill, senior author of the paper, emphasized the significance of the findings: “This is incredibly exciting research which gives us far greater detail on how genes involved in dementia are expressed in the brain and reveals potential new drug targets for treating Alzheimer’s disease that could one day disable the mechanism by which the tau accumulates. The more we learn about the way Alzheimer’s disease genes are expressed in the brain, the more we realize how much more there is to discover, and this paper is a significant step along that path.”
Original Publication
Leung, S.K., Bamford, R.A., Jeffries, A.R. et al. Long-read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology. Nat Commun 15, 6458 (2024). https://doi.org/10.1038/s41467-024-50486-8
Advanced Sequencing Techniques
The study, published in Nature Communications and funded by Alzheimer’s Research UK, the Medical Research Council, and the NIHR Exeter Biomedical Research Centre, employed cutting-edge long-read sequencing technology. This method can read longer and more complex sequences of genetic material in a single run than previously possible. The Exeter team combined this with newly developed data analysis tools to map the diversity of gene isoforms in the brains of mice engineered to carry a human mutant form of the tau protein.
Isoform Discovery and Implications
The research uncovered hundreds of new isoforms of genes implicated in Alzheimer's disease, with specific isoforms associated with tau accumulation. Notably, many isoforms identified in the mice were also differentially expressed in tissue samples from human donors who had died of Alzheimer’s. This cross-species validation underscores the relevance of the findings to human brain biology.
“Advances in technology are allowing us to map out molecular changes in the brain in greater detail than ever before,” said lead author Szi Kay Leung. “Through that we’re learning that the complex pathway of gene expression is key in the development of Alzheimer’s and could also hold the key to new treatments. We’ve made our analysis pipeline available as a resource to the community to stimulate further research in this area.”
Building on Previous Work
This study builds on previous work by the Exeter team, which identified thousands of new brain isoforms linked to various diseases. The current research delves deeper into the role of alternative splicing—a process generating different gene versions by combining various parts of the coding sequence. Understanding these mechanisms is crucial for developing therapeutic strategies targeting specific gene isoforms.
Future Directions
Jonathan Mill, senior author of the paper, emphasized the significance of the findings: “This is incredibly exciting research which gives us far greater detail on how genes involved in dementia are expressed in the brain and reveals potential new drug targets for treating Alzheimer’s disease that could one day disable the mechanism by which the tau accumulates. The more we learn about the way Alzheimer’s disease genes are expressed in the brain, the more we realize how much more there is to discover, and this paper is a significant step along that path.”
Original Publication
Leung, S.K., Bamford, R.A., Jeffries, A.R. et al. Long-read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology. Nat Commun 15, 6458 (2024). https://doi.org/10.1038/s41467-024-50486-8