Mutation and Overexpression: The Formula That Triggers Prions
A new article published by scientists from IRTA-CReSA and CICbioGUNE describes the creation and study of two new mouse models to better understand how prion diseases form spontaneously and why some prions are transmitted more easily than others.
Context: What Are Prion Diseases?
Prion diseases (such as scrapie, bovine spongiform encephalopathy, or Creutzfeldt–Jakob disease) are fatal neurodegenerative disorders caused by a normal protein (PrP) that adopts an abnormal, misfolded form. This pathological form can “convert” other normal proteins into the same defective conformation, propagating disease.
Some forms are infectious; others arise spontaneously or are associated with genetic mutations. Understanding how this spontaneous conversion begins is one of the major challenges in the field.
What Did the Authors Do?
The study focuses on a very specific substitution in mouse prion protein: the replacement of one amino acid (leucine) with another (isoleucine) at position 108 (L108I).
To analyze its effect, two models were generated:
- A transgenic model overexpressing the L108I variant (3x more protein than normal).
- A knock-in model carrying the same variant but expressed at physiological levels (1x).
This design makes it possible to separate the effect of the mutation itself from that of protein quantity.
Main Results
- The Combination of Mutation + Overexpression Induces Spontaneous Disease
All mice overexpressing the L108I variant developed spontaneous neurological disease between 7 and 18 months of age, with 100% penetrance.
In contrast, mice carrying the same mutation but expressing normal protein levels did not develop disease, even after more than 600 days.
This demonstrates that:
- The L108I substitution increases the propensity for misfolding.
- But elevated protein levels are required to trigger spontaneous disease.
- The Type of Prion Generated Is “Atypical”
The spontaneously generated prions in this model display biochemical features distinct from classical prions:
- A low molecular weight protease-resistant fragment (7–10 kDa).
- A pattern similar to atypical scrapie (Nor98) in small ruminants.
- Also similar to certain forms of Gerstmann–Sträussler–Scheinker (GSS) syndrome in humans.
This reinforces the idea that many spontaneous cases, in both animals and humans, may correspond to “atypical” conformations.
- Changes in Transmissibility
The spontaneously generated prions:
- Transmit very efficiently to mice expressing the I108 variant.
- Encounter a marked transmission barrier in wild-type mice (with L108).
Moreover, the L108I 3x model acts as a highly permissive recipient for different prion strains, both atypical and classical (RML, 22L, GSS A117V), often with shorter incubation times than in normal mice.
Not all strains behave the same way: the L108I substitution greatly accelerates propagation of some (such as RML) but barely affects others (such as 22L). This indicates that small differences in the PrP sequence can selectively modulate replication depending on the strain.
Why Is It Relevant?
This work is important for several reasons:
- Model of spontaneous onset
It provides a robust system to study how a prion disease can begin without external infection. - Understanding transmission barriers
It shows how a single amino acid can profoundly alter susceptibility and strain selection. - Connection to natural atypical forms
It reinforces the idea that certain atypical forms in sheep or humans may share a similar molecular basis: polymorphisms that favor misfolding under specific conditions. - Versatile experimental platform
The L108I overexpression model is particularly useful as a “universal amplifier” to study new strains, adaptation, prion evolution, and potential therapeutic strategies.
Key Message for the Reader
A single microscopic change — one letter in the genetic code — can increase a protein’s tendency to adopt pathological forms. But for disease to arise spontaneously, mutation alone is not enough: the amount of protein available also matters.
This study helps clarify how spontaneous prion diseases may emerge and how subtle molecular differences can shape transmission and strain evolution.
You can read the paper here: http://doi.org/10.1111/bpa.70083
El projecte EFA031/01 NEURO-COOP ha estat cofinançat en un 65% per la Unió Europea a través del Programa Interreg VI-A Espanya-França-Andorra (POCTEFA 2021-2027). L’objectiu del POCTEFA és reforçar la integració econòmica i social de la zona fronterera Espanya-França-Andorra. Pressupost total: 1.824.070,45 euros. Subvenció del FEDER: 1.185.645,78 euros.
Le projet EFA0312/01 NEURO-COOP a été cofinancé à 65% par l’Union européenne à travers le Programme Interreg VI-A Espagne-France-Andorre (POCTEFA 2021-2027). L’objectif de POCTEFA est de renforcer l’intégration économique et sociale de la zone frontalière Espagne-France-Andorre. Budget total : 1.824.070,45 euros. Subvention FEDER : 1.185.645,78 euros.
