Motor behavioral and neuropathological deficits in mice deficient for normal prion protein expression

Abstract

It has been difficult to reconcile the absence of pathology and apparently normal behavior of mice lacking prion protein (PrP), referred to as Prnp(0/0) mice, with a mechanism of prion pathogenesis involving progressive loss of PrP(C)-mediated neuroprotection. However, here we report that Prnp(0/0) mice exhibit significant age-related defects in motor coordination and balance compared with mice expressing wild type Prnp on a syngeneic background, and that the brains of behaviorally-impaired Prnp(0/0) mice display the cardinal neuropathological hallmarks of spongiform pathology and reactive astrocytic gliosis that normally accompany prion disease. Consistent with the appearance of cerebellar ataxia as an early symptom in patients with Gerstmann-Sträussler-Scheinker syndrome (GSS), an inherited form of human prion disease, motor coordination and balance defects manifested in a transgenic (Tg) mouse model of GSS considerably earlier than the onset of end-stage neurodegenerative disease. Our results are consistent with a mechanism in which loss of normal PrP(C) function is an important pathological component of prion diseases.

Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice

“…Thus, differing results in such tests were absent between wild-type and PrP C -null genotypes at 8 -12 weeks of age, but apparent in older animals (60,61). Other groups also reported age-dependent motor deficits restricted to aged PrP C -null mice (62, 63).…”

Cerebral White Matter Disruption in Creutzfeldt-Jakob Disease

“…This finding has now been extended to the early development of Prnp 0/0 mice, which display deficits in motor coordination and balance and vacuolation in several WM tracts at age 6 months. 29 In the human brain, pathologic studies of terminal CJD reported axonal damage, and suggested the possibility of retrograde axonal transport of prions, infecting multiple sites along neuroanatomic pathways. 27,[30][31][32] In the Japanese panencephalopathic variant (pCJD), WM damage has been noted in the internal capsule, brain stem, and middle cerebellar peduncles, 33 consistent with our imaging findings.…”

Prion and TNFα: TAC(E)it agreement between the prion protein and cell signaling

“…[5][6][7] Other than resistance to prion infection, 8 these animals display only marginal, if any, phenotypes in lifespan, development or behavior. 9,10 On the other hand, the possibility exists that a hidden phenotype becomes manifest only under defined stress conditions. However, the conservation of PrP C in the vertebrate sub-phylum and its ubiquitous tissue expression, argue against the possibility that PrP C may have been evolutionarily selected to only enable the onset and transmission of these fatal brain disorders.…”