Researchers at the University of Kentucky Sanders-Brown Center on Aging are working to develop a pre-symptomatic disease diagnostic tool for Alzheimer鈥檚 disease.
鈥淲hile the need for better treatments is clear, such treatments will not be very meaningful if they are administered after symptoms have onset. By then, Alzheimer鈥檚 disease has been ravaging the brain for decades to the point the brain can no longer compensate for the extreme cellular death,鈥 said Mark T. W. Ebbert, PhD, Sanders-Brown faculty and an associate professor in the Department of Internal Medicine in the College of Medicinewith a joint appointment in the Department of Neuroscience.
Ebbert is leading the research team behind the study titled 鈥淢apping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq鈥 that was recently published in .
He is also the principal investigator on multiple awards totaling nearly $5 million from the along with grants from the Alzheimer鈥檚 Association, the BrightFocus Foundation and PhRMA Foundation that funded that project.
Ebbert鈥檚 team includes lead authors Bernardo Aguzzoli Heberle, a PhD candidate at Sanders-Brown, and Jason A. Brandon, PhD, a scientist at Sanders-Brown and the Department of Internal Medicine.
The team is using a cutting-edge technique known as long-read sequencing. These technologies allow for a new level of analysis of DNA and RNA, which is the molecule that helps translate genetic code from DNA into proteins.
A single human gene can produce multiple different RNA and protein molecules, called isoforms, allowing it to perform multiple functions. Long-read sequencing helps Sanders-Brown researchers identify and measure these RNA isoforms from a single gene across the entire genome. This also overcomes technical limitations from standard short-read sequencing.
鈥淎s a proof of principle, we sequenced aged frontal cortex brain tissue 鈥 both healthy brains and brains with Alzheimer鈥檚 disease. Our team identified 99 RNA isoforms that were either increased or decreased in Alzheimer鈥檚 brains, even when the overall gene activity didn鈥檛 change,鈥 said Ebbert. 鈥淭his shows the importance of understanding isoforms and their unique functions in a gene along with their roles in human health and disease. In fact, we found more than 1,900 genes expressing multiple RNA isoforms related to human disease.鈥
The team at Sanders-Brown found some of those genes are medically relevant in brain-related diseases, including Alzheimer鈥檚 disease, Parkinson鈥檚 disease, autism spectrum disorder and substance use disorder.
鈥淭his step in understanding the human genome is exciting, but it is simply not enough. We have so much more to do to understand how individual RNA isoforms are involved in diseases, including Alzheimer鈥檚 disease, and how to target them therapeutically. There is so much work to do if we are going to defeat Alzheimer鈥檚 disease,鈥 said Ebbert.
The team also discovered five new, complex RNA variants from mitochondrial DNA. Researchers believe this is the first study to identify this genetic material in human tissue.
鈥淎lthough their expression is low, these genes could serve as biomarkers for mitochondrial function, which play an important role in many age-related diseases. It鈥檚 crucial to understand the role these new isoforms play in human health and disease,鈥 said Ebbert.
Sanders-Brown scientists hope these findings can lead to new and more precise targets for disease treatment and diagnosis across a broad range of complex human diseases.
鈥淲ith this method, we鈥檝e shown there鈥檚 potential to specifically target isoforms that are either promoting cellular health or dysfunction rather than treating a gene as a single entity,鈥 said Ebbert. 鈥淭he analysis can also help us reveal unique signatures in Alzheimer鈥檚 disease not detectable at the gene level.鈥
Researchers say larger studies are needed to better understand the RNA patterns in complex diseases and deep long-read RNA sequencing will be a necessary tool for that work.
鈥淲e are also incredibly grateful to the patients who鈥檝e donated to the 好色先生 Alzheimer鈥檚 Disease Center Tissue Bank,鈥 said Ebbert. 鈥淲ithout their participation, this level of scientific study would not be possible.鈥
This study brought together a team of researchers from the 好色先生 College of Medicine鈥檚 Department of Pharmacology and Nutritional Sciences; Department of Pathology and Laboratory Medicine; and Department of Microbiology, Immunology, and Molecular Genetics; Emory University School of Medicine in Georgia; University College of London in the United Kingdom; Cold Spring Harbor Laboratory in New York; and the Mayo Clinic in Arizona.
The full study can be found .