Central OC Times

A team led by researchers at the University of California, Irvine has identified molecular mechanisms that contribute to RNA processing defects associated with Huntington's disease (HD). These findings may facilitate collaboration among neurodegenerative disorder researchers and promote the sharing of therapeutic strategies across diseases.

Huntington's disease is known to result from an abnormal expansion of nucleotide repeats in the gene responsible for HD. However, the complexity of how this mutation disrupts cellular functions remains a challenge. The study, published in Nature Neuroscience, highlights the altered interaction between RNA-binding protein TDP-43 and m6A RNA modification on genes dysregulated in HD. TDP-43 pathology, typically linked with ALS and FTLD, was also found in HD patients' brains.

The research underscores potential therapeutic targets for neurological disorders. Leslie Thompson, Ph.D., co-corresponding author and UC Irvine Chancellor’s Professor said, “Our findings offer new insights into the role of TDP-43 and m6A modifications in contributing to defective RNA processing in HD." This research uses clinically relevant model systems to explore novel RNA-based mechanisms for gene regulation issues in HD.

Led by Thai B. Nguyen from UC Irvine, the team employed advanced genomic techniques to examine how m6A RNA modifications guide TDP-43 in regulating essential RNAs. The study utilized tissue samples from global brain banks to illuminate processes crucial for accurate RNA splicing—a key element of proper gene expression.

In both mouse models and human patients with HD, disruptions were observed in TDP-43 localization and m6A RNA modifications affecting normal RNA processing. Robert Spitale, Ph.D., co-corresponding author stated: “By targeting key processes like RNA splicing and modification...we open the door to potential new treatments for neurodegenerative diseases more broadly.”

The UC Irvine scientists collaborated with Clotilde Lagier-Tourenne at Harvard University; Don Cleveland at UC San Diego; and other institutions including Columbia University, MIT, University of Auckland and Ionis Pharmaceuticals.

This work received support from several grants including those from Chan Zuckerberg Initiative’s Collaborative Pairs awards program; National Institutes of Health; Department of Defense; National Institute of Neurological Disorders and Stroke; Dake Family Foundation; Hereditary Disease Foundation postdoctoral fellowship; ALS Association postdoctoral fellowship.

UC Irvine's Brilliant Future campaign seeks $2 billion in philanthropic investment to enhance student success, health wellness research among other areas through its School of Medicine as well as School Pharmacy & Pharmaceutical Sciences.

Founded 1965 UC Irvine ranks among top public universities produces Nobel laureates contributes significantly local state economy offers diverse degree programs under leadership Chancellor Howard Gillman.