Abstract
The molecular basis for neuronal death in prion disease is not established, but putative pathogenic roles for both disease-related prion protein (PrP(Sc)) and accumulated cytosolic PrP(C) have been proposed. Here we report that only prion-infected neuronal cells become apoptotic after mild inhibition of the proteasome, and this is strictly dependent upon sustained propagation of PrP(Sc). Whereas cells overexpressing PrP(C) developed cytosolic PrP(C) aggregates, this did not cause cell death. In contrast, only in prion-infected cells, mild proteasome impairment resulted in the formation of large cytosolic perinuclear aggresomes that contained PrP(Sc), heat shock chaperone 70, ubiquitin, proteasome subunits, and vimentin. Similar structures were found in the brains of prion-infected mice. PrP(Sc) aggresome formation was directly associated with activation of caspase 3 and 8, resulting in apoptosis. These data suggest that neuronal propagation of prions invokes a neurotoxic mechanism involving intracellular formation of PrP(Sc) aggresomes. This, in turn, triggers caspase-dependent apoptosis and further implicates proteasome dysfunction in the pathogenesis of prion diseases.
Highlights
IntroductionPrion diseases in which PrPSc is barely detectable have been described (9 –11), and subclinical infection where high levels of PrPSc accumulate in the absence of clinical symptoms are recognized [12]
Creutzfeldt-Jakob disease brains [8]
One of the major drawbacks of many of these studies on cytosolic PrPC is the high levels of proteasome inhibition used, which may limit any physiological relevance to the situation in vivo [26]
Summary
Prion diseases in which PrPSc is barely detectable have been described (9 –11), and subclinical infection where high levels of PrPSc accumulate in the absence of clinical symptoms are recognized [12] In such “subclinical disease states,” the majority of the accumulated PrPSc may be inert; alternatively, PrPSc may not be the toxic entity, but instead a toxic oligomeric PrP intermediate species (PrPL for lethal) may be produced during prion conversion [12]. It was proposed that prion-associated toxicity involves altered trafficking of PrPC, where inhibition of the ubiquitin-proteasome system (UPS) results in extensive PrPC accumulation in the cytoplasm and associated neuronal cell death [20]. We found evidence for similar structures in vivo in brains of prion-infected mice
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