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

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

The findings may pave the way for neurodegenerative disorder researchers to collaborate and share therapeutic strategies across diseases, opening additional avenues for treatment.

While it's known that HD is 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 highly complex.

The study, recently published online in the journal Nature Neuroscience, reveals the interplay between two key regulators of RNA processing. Binding of both the RNA-binding protein TDP-43 and the m6A RNA modification chemical tag has been found to be altered on genes that are dysregulated in HD. Further, TDP-43 pathology, classically associated with ALS and FTLD, is found in diseased brains from HD patients.

RNA modifications and how they control RNA abundance to lead to disease is an emergent and challenging area of biological research. "Our findings offer new insights into the role of TDP-43 and m6A modifications in contributing to defective RNA processing in HD. This enhanced understanding highlights their potential as therapeutic targets, which are major areas of research for other neurological disorders. Drugs developed to interact with these pathways could offer new hope for slowing or even reversing neurodegeneration in HD, ALS and other diseases where TDP-43 dysregulation is significant. This research is very important because it uses clinically relevant model systems to understand and elucidate novel 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 & human behavior as well as neurobiology & behavior.

Led by UC Irvine assistant project scientist Thai B. Nguyen, the team used advanced genomic and molecular biology techniques to explore how m6A RNA modifications serve as landmarks directing TDP-43 to regulate crucial RNAs. Utilizing 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 discovered that in both HD mouse models and human patients, the mislocalization of TDP-43 and alterations in m6A RNA modifications disrupt TDP-43's ability to bind to RNA correctly. This disruption leads to abnormal RNA processing and splicing errors. Further analysis revealed that these irregularities align with widespread gene disruptions, particularly in the striatum, a brain region significantly impacted by HD-related neuronal dysfunction.

By targeting key processes like RNA splicing and modification, we not only advance our understanding of the molecular disruptions behind HD but also open the door to potential new treatments for neurodegenerative diseases more broadly. It was a really important collaboration to bring chemical and genomic tools from my lab and merge them with Leslie's powerful and robust model systems to nail down this novel mechanism."

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

The UC Irvine scientists partnered with Clotilde Lagier-Tourenne, associate professor of neurology at Harvard University; Don Cleveland, chair and professor of cellular and molecular medicine at UC San Diego; and their research groups. Other team members included project scientists, faculty, and undergraduate 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 full 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 backing was provided by the National Institute of Neurological Disorders and Stroke under award number F31NS124293T32, the Dake Family Foundation, a Hereditary Disease Foundation postdoctoral fellowship, and a postdoctoral fellowship from the ALS Association.