Dangerous Stops: Nonsense Mutations Can Dramatically Increase Frequency of Prion Conversion

Area of Science:

• Molecular Biology
• Neurodegenerative Diseases
• Protein Misfolding

Background:

• Amyloid formation underlies incurable diseases, with sporadic cases often outnumbering familial ones.
• Somatic cell mosaicism is hypothesized to initiate amyloidogenesis in limited cell populations, potentially spreading through tissues.
• The specific mutations driving sporadic amyloid formation remain largely unidentified.

Purpose of the Study:

• To identify mutations that enhance the de novo appearance of amyloids.
• To investigate the role of truncated amyloidogenic proteins in sporadic amyloid disease initiation.

Main Methods:

• Utilized yeast prionogenic protein Sup35 as a model system.
• Introduced mutated copies of the SUP35 gene into yeast cells.
• Analyzed the prion incidence resulting from specific mutations and mRNA splicing events.

Main Results:

• Certain nonsense mutations in the SUP35 gene significantly increased prion incidence.
• This effect correlated with the exposure of an internal amyloidogenic region at the C-terminus.
• Discovered inefficient splicing of SUP35 mRNA produces a highly prionogenic truncated isoform.

Conclusions:

• Truncated amyloidogenic proteins, arising from nonsense mutations or alternative splicing, can initiate localized amyloid formation.
• These findings suggest a mechanism for sporadic amyloid disease initiation via somatic mutations or splicing events.
• This research provides insights into the origins of sporadic amyloid diseases.