A research group has revealed complex molecular processes responsible for RNA processing issues that result in Huntington’s disease and connect it with other neurodegenerative conditions like amyotrophic lateral sclerosis, frontotemporal lobar dementia, and Alzheimer’s disease.
A team led by the University of California, Irvine, has unveiled complex molecular mechanisms that contribute to RNA processing issues leading to Huntington’s disease and associated links to other neurodegenerative conditions such as amyotrophic lateral sclerosis, frontotemporal lobar dementia, and Alzheimer’s disease.
The discoveries could foster collaboration among researchers focused on neurodegenerative diseases, allowing them to share treatment strategies and open new paths for therapies.
Although it is established that Huntington’s disease (HD) arises from an abnormal expansion of cytosine, adenine, and guanine nucleotide repeats in the HD gene’s DNA, the way this mutation disrupts cellular functions is quite intricate.
In a study published in the journal Nature Neuroscience, the researchers explored how two vital regulators of RNA processing interact with each other. They found that the binding patterns of the RNA-binding protein TDP-43 and the m6A RNA modification chemical tag change on genes that are malfunctioning in HD. Moreover, cases of TDP-43 pathology, typically seen in ALS and frontotemporal lobar dementia, were observed in the brains of Huntington’s disease patients.
The research into RNA modifications and their impact on RNA levels leading to disease is a developing and challenging area. “Our work provides new perspectives on the roles of TDP-43 and m6A modifications in defective RNA processing in HD. This increased understanding emphasizes their potential as targets for therapies, which are significant in the context of other neurological disorders. Drugs designed to engage with these pathways could bring new hope for slowing or reversing neurodegeneration in HD, ALS, and other diseases heavily influenced by TDP-43 irregularities. This study is crucial as it employs clinically relevant models to uncover and clarify new RNA-based mechanisms that cause improper gene regulation in HD,” stated Leslie Thompson, Ph.D., the co-corresponding author, Chancellor’s Professor and Donald Bren Professor of psychiatry & human behavior, as well as neurobiology & behavior at UC Irvine.
Under the leadership of UC Irvine assistant project scientist Thai B. Nguyen, the team employed cutting-edge genomic and molecular biology methods to investigate how m6A RNA modifications guide TDP-43 in regulating essential RNAs. Utilizing valuable tissue samples from global brain banks, the study illuminates a process critical for accurate RNA splicing, which is fundamental to appropriate gene expression.
The researchers found that in both HD mouse models and human patients, the improper localization of TDP-43 and changes in m6A RNA modifications hinder TDP-43’s ability to correctly bind to RNA. This leads to irregular RNA processing and splicing mistakes. Additional analysis indicated that these anomalies correlate with extensive gene disruption, especially in the striatum, a brain area significantly affected by neuronal dysfunction related to HD.
“By focusing on crucial processes like RNA splicing and modifications, we not only enhance our comprehension of the molecular disruptions linked to HD but also pave the way for potential new treatments for broader neurodegenerative diseases. It was a vital collaboration that combined chemical and genomic tools from my lab with Leslie’s strong and effective model systems to identify this new mechanism,” remarked co-corresponding author Robert Spitale, Ph.D., UC Irvine’s founding associate dean of research and a professor of pharmaceutical sciences.
The researchers from UC Irvine collaborated with Clotilde Lagier-Tourenne, an associate professor of neurology at Harvard University; Don Cleveland, chair and professor of cellular and molecular medicine at UC San Diego; along with their research teams. Additional contributors included project scientists, faculty, and undergraduates 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 the complete list.
This research received funding from the Chan Zuckerberg Initiative’s Collaborative Pairs awards; National Institutes of Health grants R35 NS116872, R01 NS112503, R01 NS124203, R01 NS27036, R01 AA029124, and K22CA234399; and a Department of Defense grant TS200022. Further support was given by the National Institute of Neurological Disorders and Stroke under F31NS124293T32, the Dake Family Foundation, a Hereditary Disease Foundation postdoctoral fellowship, and a postdoctoral fellowship from the ALS Association.
