Spontaneous generation of prions and transmissible PrP amyloid in a humanized transgenic mouse model of A117V Gerstmann-Sträussler-Scheinker (GSS)

“Consensus science” is the risky situation whereby “a majority of ‘scientists’ might agree upon a ‘fact’ they fervently believe to be true.” The consensus may or may not turn out to be confirmed by further research, but we should remember that science is never completely irrefutable. For example, “mad cow disease” [and the human equivalent, CJD (Creutzfeldt-Jakob Disease)] — was a degenerative brain disease of unknown cause. After more than a decade of studies, neurologist Stanley Prusiner reported in 1982 that these diseases were caused by a virus-like protein, which he named “prion” (derived from “protein” and “infectious”). He was ridiculed by at least 99% of the scientific world, because “viruses are well known always to comprise DNA or RNA.” Prusiner persisted, however, because he was convinced the consensus was wrong. In 1997 he was awarded the Nobel Prize for Medicine or Physiology for his novel discovery; prions are now realized to affect tissues other than brain and, in fact, are found even in lower organisms — such as yeast…!! ☹

Prions are known to cause other fatal neurodegenerative diseases in mammals, such as scrapie in sheep and goats, and bovine spongiform encephalopathy (BSE) in cattle. Prions are unique pathogens in that they are composed of infectious assemblies of misfolded host-encoded prion protein (PrP). Prions propagate via seeded protein polymerization (a process that involves addition of PrP monomers to an elongating assembly of misfolded PrP chains, followed by fission of the polymer to produce more “seeds”). Human prion diseases are associated with a range of clinical presentations — classified by both clinico-pathological syndrome and etiology. About 15% of cases are associated with autosomal dominant pathogenic mutations in the human prion protein gene (PRNP), and, to date, more than 40 mutations have been described. How pathogenic mutations in PRNP cause inherited prion disease has yet to be resolved (however, in most cases, the mutation is thought to lead to spontaneous conformational change in the expressed protein, leading to the generation of disease-related PrP assemblies that propagate by seeded protein misfolding).

Many studies of acquired or sporadic CJD indicate that a residue-129 polymorphism of human PrP critically dictates thermodynamic preferences for PrP assemblies associated with human distinct prion strains; yet, the full spectrum of effects that different pathogenic PRNP mutations have — remains unclear. Notably, a common feature of PRNP point mutations associated with conspicuous amyloid PrP plaque deposition in brain — is that the expressed full-length mutant PrP forms two distinct disease-related assemblies of misfolded PrP: [a] one assembly forms N-terminally truncated protease-resistant fragments that correspond to those generated from classical PrP 27–30, which is enriched in brain areas showing synaptic PrP deposition, spongiform vacuolation, and neurodegeneration; [b] the other disease-associated assembly forms smaller N- and C-terminally truncated protease-resistant fragments associated with PrP amyloid plaques.

The proposed mechanism is that the mutation predisposes to conformational change in the expressed protein, leading to the generation of disease-related multichain PrP assemblies that propagate by seeded protein misfolding. Despite considerable experimental support for this hypothesis — until now, spontaneous formation of disease-relevant transmissible PrP assemblies in transgenic models expressing only mutant human PrP has not been demonstrated. Authors [see attached article] report findings from transgenic mice that express human PrP 117V on a mouse PrP null background (117VV Tg30 mice), which models the PRNP A117V (alanine-to-valine) mutation causing inherited prion diseases, including the Gerstmann-Sträussler-Scheinker (GSS) disease phenotype in humans.

By studying brain samples from uninoculated groups of mice, authors discovered that some elderly mice (> 475 days old) spontaneously generated abnormal PrP assemblies, which — after inoculation into further groups of 117VV Tg30 mice — produced a molecular and neuropathological phenotype consistent with that seen after transmission of brain isolates from inherited prion disease A117V patients to the same mice. Authors believe this 117VV Tg30 mouse line is the first transgenic model expressing only mutant human PrP to show spontaneous generation of transmissible PrP assemblies that directly mirror those generated in an inherited clinical prion disease. 😊😊


PLoS Biol June 2020; 18: e3000725

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