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Modulation of prion protein expression through cryptic splice site manipulation.
Juliana E Gentile1, Taylor L Corridon1, Meredith A Mortberg1
1McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
The Journal of Biological Chemistry
|July 13, 2024
Summary
Researchers identified a cryptic exon in the prion protein gene (PRNP) that can be utilized to reduce prion protein (PrP) expression. This finding offers a novel therapeutic strategy for prion diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Lowering prion protein (PrP) expression is a validated therapeutic strategy for prion diseases.
- Small molecules can modulate pre-mRNA splicing to affect gene expression, offering alternative therapeutic avenues.
Purpose of the Study:
- To characterize a cryptic exon in the human PRNP gene.
- To evaluate its potential for reducing PrP expression via incorporation into the 5' untranslated region.
Main Methods:
- A minigene transfection system was established.
- A panel of splice site alterations were tested to assess their impact on PrP expression.
Main Results:
- A cryptic exon was identified in the sole intron of the human PRNP gene.
- Mutants incorporating this exon reduced PrP expression by up to 78% through mechanisms like translational repression or nonsense-mediated decay.
- The exon contains a start codon leading to an upstream open reading frame and a premature stop codon.
Conclusions:
- The identified cryptic exon represents a novel therapeutic target for lowering PrP expression.
- This approach offers a new strategy for developing treatments for prion diseases.
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