Summary: Mutations that produce abnormal RNA from repeated DNA sequences trigger an antiviral-like inflammatory response in cells. This immune activation causes neuronal cell death and can lead to progressive neurodegenerative disease.

Source: University of Adelaide

Researchers identify how DNA repeat mutations trigger neurodegeneration

Scientists have uncovered a cellular mechanism linking DNA repeat mutations to neurodegenerative diseases such as Huntington’s disease and some forms of motor neurone disease. The finding points to a new, shared pathway of disease progression and suggests potential opportunities to repurpose anti-inflammatory strategies to slow or delay symptoms.

A multidisciplinary team led by the University of Adelaide reports experimental evidence that expanded repeat mutations produce abnormal double-stranded RNA (dsRNA) that the cell recognises as “non-self.” This misidentification activates an antiviral-like inflammatory response that drives neuronal damage and cell death, ultimately producing progressive neurological decline. The study appears in Human Molecular Genetics and builds on more than a decade of collaborative research, including partners at the Victor Chang Research Institute.

One mechanism, many diseases

DNA repeat disorders — sometimes called “repeat expansion” diseases — include Huntington’s disease and over 20 other inherited neurodegenerative conditions. Although these diseases share clinical features, the molecular steps linking mutation to neuronal dysfunction were not well understood and were often treated as distinct processes. This new work demonstrates that expanded repeat regions in DNA can generate abnormal dsRNA that triggers the same intracellular inflammatory pathway across different disorders.

“If the new mechanism we have discovered proves to be correct, it will transform the field, providing a different way of thinking about these diseases and offering new opportunities for medical intervention.”

How abnormal RNA elicits inflammation

The research focuses on RNA, the cellular molecule that carries genetic instructions from DNA to the protein-making machinery. Under normal conditions, cellular RNAs are chemically modified—“bar-coded”—so the innate immune system recognises them as self and does not mount an inflammatory response. When DNA repeats expand, they can produce double-stranded RNA structures that escape this self-identification.

Using a Drosophila (fruit fly) model, Professor Rob Richards and colleagues showed that repeat-derived dsRNA is treated by the cell’s defence machinery as foreign. Dicer2 recognises the dsRNA and activates both antiviral RNA and RNA interference (RNAi) pathways. The investigators demonstrated that inflammation and neuronal pathology arise from this antiviral-like response rather than normal RNAi cofactors, implicating an innate antiviral surveillance mechanism.

The team also found that RNA editing prevents this harmful recognition: human ADAR1 edits RNA to confer “self” status, and co-expressing ADAR1 with the expanded repeat dsRNA in flies prevented the pathology. Similarly, expressing a viral antagonist of Argonaute2 (CrPV-1A) rescued the disease phenotype, further confirming that an antiviral RNA response is responsible for the damage.

Therapeutic implications

Because the damaging step appears to be an innate inflammatory reaction to endogenous dsRNA, existing anti-inflammatory and immunomodulatory drugs used for other autoinflammatory disorders might be repurposed to reduce pathology in repeat expansion diseases. Targeting the antiviral-like inflammatory pathway could slow neuronal loss and delay symptom onset. The authors caution that additional research is needed to translate these findings from Drosophila models to humans, but the results point to a unifying, proximal trigger for a range of neurodegenerative conditions.

Source:
University of Adelaide
Media contact:
Rob Richards – University of Adelaide
Image source:
Public domain

Original research: Closed access. Article: “’Non-self’ Mutation: Double-stranded RNA elicits antiviral pathogenic response in a Drosophila model of expanded CAG repeat neurodegenerative diseases.” Robert I Richards et al., Human Molecular Genetics. DOI: 10.1093/hmg/ddz096

Abstract summary: Inflammation precedes clinical symptoms in many neurodegenerative diseases and is required for pathology in animal models. Expanded CAG/CUG repeat dsRNA causes inflammation-mediated pathology in Drosophila by being recognised as foreign by Dicer2, activating antiviral RNA and RNAi pathways. RNA editing by ADAR1 prevents recognition as non-self and eliminates pathology; antagonising components of the antiviral response also rescues the phenotype. These findings identify repeat expansion as a proximal autoinflammatory trigger for expanded repeat neurodegenerative diseases.