What was discovered?
- These mutations affect a cellular complex called the RNA exosome, which plays a critical role in RNA processing, surveillance, and degradation.
- This reveals the potential to use yeast as a model organism for studying human neurological disorders, particularly those related to RNA exosome dysfunction.
What are RNA Exosomopathies?
- RNA exosomopathies are disorders caused by mutations in genes coding for RNA exosome components.
- These disorders primarily lead to brain maldevelopment, affecting structures like the pons and cerebellum.
- A key example is Pontocerebellar Hypoplasia Type 1 (PCH1), which results in severe motor, cognitive, and developmental impairments in infants.
Role of the RNA Exosome
- The RNA exosome is a multi-protein complex discovered in yeast in 1997.
- It is responsible for:
- Processing, surveillance, and degradation of different types of RNA molecules.
- Maturation of ribosomal RNA (rRNA) – essential for building ribosomes.
- Elimination of faulty messenger RNA (mRNA) and regulation of non-coding RNAs (ncRNA).
Experimental Findings (Study 1 – Journal RNA)
- Researchers introduced human disease mutations into corresponding yeast genes.
- Found defects in:
- RNA surveillance
- Ribosome production
- Protein synthesis
- Each mutation had a distinct molecular signature, explaining the varied clinical symptoms in patients.
Creation of a Humanised Yeast Model (Study 2 – Journal G3)
- Scientists replaced segments of yeast RNA exosomes with human or mouse genes.
- Of 9 core proteins, 6 were successfully replaced, with 3 supporting normal yeast growth.
- Introduced known brain-defect mutations into this model.
- Proved that mutations directly impair RNA exosome function and are not mediated through indirect processes.
Why Yeast?
- Yeast is a simple eukaryote, easy to genetically modify and culture.
- Offers a cost-effective and fast method for testing hypotheses and potential drug interventions.
- Using yeast models allows rapid screening of RNA exosome mutations and their functional consequences.
