Revealed: toxic RNA's role in Huntington's disease

Researchers from The Chinese University of Hong Kong (CUHK), in collaboration with the University of Illinois at Urbana-Champaign and the University of Pisa, have unveiled how a special RNA species called small CAG repeat RNA (sCAG) plays a destructive role in the pathogenesis of Huntington’s disease (HD) by causing damage to the genetic materials in the genome. Published in the journal PNAS, this is claimed to be the first study that demonstrates sCAGs are sufficient to induce neuronal DNA damage.

HD is an adult-onset genetic disorder, with symptoms usually starting when patients are in their mid-30s or 40s. As the disease advances, patients experience progressive decline of their body movement control and cognitive thinking ability due to the continuous malfunctioning of nerve cells in their brains; some patients further experience psychiatric disturbances. Medications are only for symptoms management, and at this moment HD remains an incurable condition.

Professor Edwin Chan and the CUHK team showed that when sCAG accumulates in nerve cells at a high enough level, the normal function of NUDT16, an important factor responsible for safeguarding the integrity of the genome, will be compromised. Reducing NUDT16 functionality results in rapid accumulation of genome damage in the brain cells and eventually triggers neuronal degeneration and cell death. On the other hand, restoring the normal function of NUDT16 can rescue DNA damage and apoptosis in HD models.

The team further discovered a small molecule compound termed DB213, which can significantly restore motor deficits in mice that contract HD. Using nuclear magnetic resonance spectroscopy, the team determined the solution structure of the DB213/sCAG complex, enabling them to visualise how the compound docks onto the toxic sCAG. This technology provides a basis for the team to further modify the compound for achieving higher therapeutic effects against HD.

“Our team is very grateful for being able to put one more jigsaw piece to the puzzle in explaining how HD comes about,” Prof Chan said. “Our research findings further enable us to apprehend, at the atomic level, how the DB213 small molecule neutralises RNA toxicity and relieves HD symptoms.

“When the compound was administered to primary neurons and diseased mice using an intranasal route application, we found that the compound significantly suppresses DNA damage in the cells and restores the behavioural phenotypes in diseased mice. We are happy to see that this compound can go to the brain by itself when applied through the nostrils, further highlighting its therapeutic potential.

“We are now ready to bring this study to the preclinical stage. Other than HD, our compound can also be utilised in several types of spinocerebellar ataxias, another group of rare neurological diseases.”

Image credit: ©stock.adobe.com/au/ralwel

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