Researchers uncover molecular mechanisms driving RNA processing defects in Huntington’s disease

A University of California, Irvine-led research team has discovered complex molecular mechanisms driving the RNA processing defects that lead to Huntington’s disease and link HD to other neurodegenerative disorders such as amyotrophic lateral sclerosis, frontotemporal lobar dementia and Alzheimer’s disease.

The findings could pave the way for researchers in the field of neurodegenerative diseases to collaborate and share therapeutic strategies for different diseases, opening additional avenues for treatment.

Although HD is known to be caused by an abnormal expansion of cytosine, adenine and guanine nucleotide repeats in the DNA of the gene responsible for HD, How this mutation interferes with cellular functions is very complex.

The study, recently published online in the journal Nature Neurosciencereveals the interplay between two key regulators of RNA processing. Binding of both the RNA-binding protein TDP-43 and the chemical tag for m6A RNA modification have been found to be altered on genes disrupted in HD. Furthermore, TDP-43 pathology, classically associated with ALS and FTLD, is found in diseased brains of HD patients.

RNA modifications and how they control RNA abundance to lead to disease is an emerging and challenging area of ​​biological research. “Our findings provide new insights into the role of TDP-43 and m6A modifications in contributing to defective RNA processing in HD. This improved understanding highlights their potential as therapeutic targets, which are important areas of research for other neurological disorders. Drugs designed to interact with these pathways could offer new hope for slowing or even reversing neurodegeneration in HD, ALS and other diseases where dysregulation of TDP-43 is significant. This research is very important because it uses clinically relevant model systems to understand and elucidate emerging disease RNA-based mechanisms for aberrant gene regulation in HD,” said co-corresponding author Leslie Thompson, Ph.D., UC Irvine Chancellor’s Professor and Donald Bren Professor of psychiatry and human behavior, as well as neurobiology and behavior.

Led by UC Irvine assistant project scientist Thai B. Nguyen, the team used advanced genomic and molecular biology techniques to investigate how m6A RNA modifications serve as landmarks that direct TDP-43 to regulate crucial RNAs. Using invaluable tissue samples from global brain banks, the study sheds light on a process essential for accurate RNA splicing – a cornerstone of proper gene expression.

The researchers found that in both HD mouse models and human patients, TDP-43 mislocalization and changes in m6A RNA modifications disrupt TDP-43’s ability to properly bind to RNA. This disruption leads to abnormal RNA processing and splicing errors. Further analysis revealed that these irregularities align with widespread gene disruptions, especially in the striatum, a brain region significantly affected by HD-related neuronal dysfunction.

By targeting key processes such as RNA splicing and modification, we not only increase our understanding of the molecular perturbations behind HD, but also open the door to potential new treatments for neurodegenerative diseases more broadly. It was a very important collaboration to take chemical and genomic tools from my laboratory and merge them with Leslie’s powerful and robust model systems to capture this new mechanism.”

Robert Spitale, Ph.D., co-corresponding author, founder of UC Irvine, associate dean of research and professor of pharmaceutical sciences

The UC Irvine scientists worked with Clotilde Lagier-Tourenne, associate professor of neurology at Harvard University; Don Cleveland, chairman and professor of cellular and molecular medicine at UC San Diego; and their research groups. Other team members included project scientists, faculty and graduate students from UC Irvine, Columbia University, the Massachusetts Institute of Technology, the University of Auckland and Ionis Pharmaceuticals in Carlsbad. Click here for a complete list.

This work was supported by the Chan Zuckerberg Initiative’s Collaborative Pairs awards program; National Institutes of Health grants R35 NS116872, R01 NS112503, R01 NS124203, R01 NS27036, R01 AA029124, and K22CA234399; and Department of Defense grant TS200022. Additional support was provided by the National Institute of Neurological Disorders and Stroke under award number F31NS124293T32, the Dake Family Foundation, a postdoctoral fellowship from the Hereditary Disease Foundation, and a postdoctoral fellowship from the ALS Association.