Study uncovers RNA changes in Alzheimer’s disease
Researchers at McGovern Medical School have gained insights about what happens inside brain cells during Alzheimer’s disease (AD), a devastating neurodegenerative disorder. Their findings, published in the journal Nature Communications on June 6, could help scientists better understand and eventually treat this condition.
“Rewired m6A of promoter antisense RNAs in Alzheimer’s disease regulates neuronal genes in 3D nucleome” was published in the June 6 issue by first authors Benxia Hu and Yuqiang Shi, and the last author that directed this work is Wenbo Li, PhD, associate professor of biochemistry and molecular biology.
This work further develops the field of “epitranscriptomics” – the study of RNA chemical modifications. While much work has been devoted to this area over the past decade to study basic RNA biology, such RNA modifications and their functions in the human brain and Alzheimer’s have been minimally explored.
The research team generated RNA profiling data from brain tissue samples from 12 people who had died—six with Alzheimer’s disease and six without. An antibody that recognizes a key RNA chemical modification, N6-methyladenosine, also called m6A, allowed the team to study where the RNA chemical modification takes place on all human brain RNAs in normal or in AD conditions
The scientists discovered that certain RNA molecules, called promoter-antisense RNAs, behave very differently in brains affected by Alzheimer’s. These RNAs don’t make proteins themselves, but they help control which genes get turned on or off—like a dimmer switch for genetic activity.
One particular RNA molecule caught their attention: MAPT-paRNA. This RNA is especially active in neurons and becomes much more active in Alzheimer’s brains. This RNA doesn’t directly control the tau protein—a known hallmark of Alzheimer’s that forms tangles in brain cells. Instead, it acts like a master controller, influencing about 200 different genes throughout the genome. What makes this discovery particularly intriguing is how this RNA works. Rather than just affecting nearby genes, MAPT-paRNA reaches across different chromosomes to influence genes far away. It does this by influencing how the DNA is folded and organized within the cell’s nucleus.
Important to AD, many of the genes controlled by this paRNA are crucial for neuron survival and the connections between brain cells. This links the changes of m6A and paRNA to AD pathology.
This research opens up new possibilities for understanding Alzheimer’s disease. Rather than focusing solely on the well-known protein culprits like tau and amyloid, scientists can now explore how RNAs and their chemical modifications contribute to the disease process. In particular, RNAs and their modifications can be exploited as novel druggable targets in the near future to treat AD.
The authors noted that even though they had a relatively large sample size of six brain samples from both normal and Alzheimer’s disease patients, more patient samples will be needed to fully understand RNA changes in AD brain.
Additional authors from McGovern Department of Biochemistry and Molecular Biology include Feng Xiong, Yi-Ting Chen, Xiaoyu Zhu, Nathan Drolet, Elisa Carrillo, and Vasanthi Jayaraman. In particular, Carrillo and Jayaraman generated crucial data showing that neuronal activity can be affected by this paRNA. Other McGovern collaborators include Dung-Fang Lee, Department of Integrative Biology and Pharmacology, and Claudio Soto, Department of Neurology. And co-authors also included, from University of California San Diego: Sheng Zhong and Xingzhao Wen; from University of California Irvine, Xiangmin Xu; and from Baylor College of Medicine, Hui Zheng and Chetan Rajpurohit.