Research News

New research from the laboratory of Feixiong Cheng, PhD, Director of the Cleveland Clinic Genome Center, has mapped out another layer of the complex risk factors that contribute to Alzheimer’s disease: post-transcriptional modification.  

In a recent Alzheimer’s and Dementia: the Journal of the Alzheimer’s Association publication, the Cheng Lab describes how a range of post-transcriptional modifications called RNA editing may serve as an understudied link between aging and neurodegeneration. These modifications, which change the molecules in our RNA, may serve as new targets for diagnosing and treating Alzheimer’s disease. 

“There is no one factor that determines how likely someone is to develop Alzheimer’s disease,” says study first author Amit Gupta, PhD, a postdoctoral fellow in the Cheng Lab. “Many factors influence critical biological processes including genetics, proteomics, protein-protein interactions, environment, aging, health history and medication usage. Such a complex condition requires new and innovative approaches to tackle it, but first we need to understand understudied factors that contribute to disease risk.” 

 What are post-transcriptional modifications? 

Post-transcriptional modifications are changes made to an RNA molecule after it is made. When our cells make or transcribe RNA, they directly read and carry out instructions encoded in our DNA, molecule by molecule. However, these instructions are often incomplete. Messenger RNA (mRNA), which our bodies use to make proteins, can have extra molecules that need to be cut. Some noncoding RNAs, which don’t make proteins, need extra molecules added to function. These modifications, and many more, are necessary for our bodies to function normally. 

RNA editing remains of great interest and has been linked to neurological conditions including Alzheimer’s disease, but the genome-wide tissue specific landscape and its impact on brain regulation remains relatively underexplored, Dr. Cheng explains. To gain more insight, Dr. Gupta and his team analyzed RNA sequencing data from more than 4,000 brain tissue samples, spanning nine distinct brain regions. They analyzed three publicly available databases and included samples from over 2,000 individuals both with and without Alzheimer’s disease. 

 What do post-transcriptional modifications do in aging brains? 

The team uncovered over one hundred signaling pathways across the brain that significantly edited mRNA transcribed from genes involved in processes like neuronal development, signaling and neuronal inflammation. These processes are critical to healthy brain function and can lead to Alzheimer’s disease when dysregulated. The team also found RNA editing signals that helped regulate almost 50 Alzheimer’s-associated genes and proteins. Together, the findings underscore the importance of post-transcriptional modifications in regulating brain cell function as we age. 

These RNA editing differences may even help resolve a longstanding question in Alzheimer’s research by explaining how certain genes can influence brain health more profoundly in some individuals than others, even when the genes themselves are not mutated. The findings suggest RNA-based biomarkers and therapies could be a new avenue for treatment strategy, Dr. Gupta says. The next step is to functionally validate the analysis’s most promising findings in the lab. 

“By deepening our understanding of the RNA-edited targets we found and the mechanisms that link these targets to disease risk, we may uncover new biomarkers and therapeutic strategies for Alzheimer’s disease and related dementias,” Dr. Cheng says. “This project reflects our Genome Center’s commitment to developing innovative genomic research strategies that look beyond genes themselves to better understand and treat complex diseases.”

For the next step, Dr. Cheng and his team are investigating how RNA editing influences protein expression, laying the groundwork for identifying novel therapeutic targets for Alzheimer’s disease and other complex conditions.