Scientists Tame Biological Trigger of Deadly Huntington’s Disease

Huntington’s disease causes involuntary movements and dementia, has no cure, and is fatal. For the first time, UC Riverside scientists have shown they can slow its progression in flies and worms, opening the door to human treatments.

Key to understanding these advancements is the way that genetic information in cells is converted from DNA into RNA, and then into proteins. DNA is composed of chemicals called nucleotides: adenine (A), thymine (T), guanine (G), and cytosine (C). The order of these nucleotides determines what biological instructions are contained in a strand of DNA.

On occasion, some DNA nucleotides repeat themselves, expanding the DNA strand. In Huntington’s disease, this expansion occurs with three nucleotides, cytosine-adenine-guanine, or CAG.

Expansion into an extraordinary number of repeated CAG sequences of DNA is associated with earlier onset and increased severity of Huntington’s disease symptoms. Similar observations were made for a number of other neurodegenerative diseases.

When these DNA repeats are translated into RNA, there is an insidious side effect. The cell chemically modifies the extra RNA buildup. Wang and his collaborators learned that the modified RNA plays a crucial role in neurodegeneration.

“We are first to discover that a type of chemical modification, called methylation, occurs more frequently with extra repeats in RNA. Then we see abnormal distribution and buildup of a particular protein in cells,” said Yinsheng Wang, distinguished UCR professor of chemistry. “In other words, methylation converts an important cellular protein into waste.”

These findings parallel observations made for the same protein in brain tissues of Huntington’s disease, ALS and frontotemporal dementia patients. Longer RNA repeats mean a higher modification rate, which generates more protein waste and exacerbates disease.

Long, repetitive RNA sequences can turn into an excess of protein in cells, creating “cellular trash,” which has toxic effects.

A new Nature journal article details how RNA methylation on CAG repeats is implicated in the complex mechanism underlying Huntington’s disease. The article also explains how the researchers greatly reduced the progression of disease in worms and fruit flies and extended the lifespan of flies by introducing a protein into cells that removes methylation.

The research team  is now searching for small molecules that can inhibit methylation and form the basis of Huntington’s therapy.

“We don’t think the mechanisms we studied are the only ones that contribute to Huntington’s,” Wang said. “However, we have shown that by targeting them we can reduce the disease in model organisms, which could lead to longer, better lives for those who suffer from this and potentially other diseases as well.”

Sources:

Yuxiang Sun, Hui Dai, Xiaoxia Dai, Jiekai Yin, Yuxiang Cui, Xiaochuan Liu, Gwendolyn Gonzalez, Jun Yuan, Feng Tang, Nan Wang, Alexandra E. Perlegos, Nancy M. Bonini, X. William Yang, Weifeng Gu, Yinsheng Wang. m1A in CAG repeat RNA binds to TDP-43 and induces neurodegeneration. Nature, 2023; DOI: 10.1038/s41586-023-06701-5

University of California – Riverside. “Scientists tame biological trigger of deadly Huntington’s disease.” ScienceDaily. ScienceDaily, 8 November 2023. <www.sciencedaily.com/releases/2023/11/231108164219.htm>.

Materials provided by University of California – Riverside. Original written by Jules Bernstein. Note: Content may be edited for style and length.

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