Neuropathogenesis of Prion Disease

Louise Davidson; Richard Knight


Future Neurology. 2014;9(2):135-147. 

In This Article


A great deal is known about the neuropathological and clinical features of prion disease; it is also known that while disease may occur sporadically, it may result from pathogenic genetic mutations and from infection. The various forms of prion disease are linked by core molecular changes involving PrP, the prion protein, with the formation of PrPSc; however, the exact mechanisms of neuronal dysfunction and neuronal death in prion disease remain uncertain. There are many proposed important functions of PrPC but loss of PrPC function does not appear to be the main pathogenic mechanism. There is significantly more evidence for direct neurotoxicity of abnormal PrP, although not simply related to the aggregated PrPSc form. Oligomeric protein species formed as intermediates between PrPC and PrPSc or increased amounts of 'aberrant' forms of PrPC are more likely toxic candidates. There is accumulating evidence that PrPC itself may have a pathological role, with its functions being subverted by abnormal or 'aberrant' forms of PrP. Interestingly, aside from the general connections with other neurodegenerative diseases (in relation to the role of potentially toxic oligemeric proteins), PrPC has been implicated directly in the neuropathogenesis of diseases other than prion disease – for example, Alzheimer's disease.[85] For example, in other neurodegenerative diseases that are associated with β-sheet rich oligomers, shedding of PrPC interferes with the neurotoxic pathway by reducing the receptor availability for the oligomeric species.[11] It has been hypothesized that Aβ oligomers bind to the N-terminus of PrPC, thereby stimulating NMDA receptors and subsequently neuronal cell death. This interaction goes on to initiate a protective mechanism. The binding of the oligomers to PrPC leads to an increase of PrPC at the plasma membrane. These toxic oligomers directly and indirectly (via PrPC) stimulate NMDA receptors. The stimulation of NMDA receptors has been linked to the upregulation of ADAM10 and, therefore, an overall increase in PrPC shedding. This hypothesis has been well illustrated in a review by Altmeppen et al. and supported by recent in vivo and in vitro studies.[12,86,87] Therefore, it has therefore been proposed that increasing the ADAM 10 mediated shedding of PrPC potentially offers a future therapeutic option.[11,12]

Interesting recent reports, extending earlier work by Mallucci, have described studies of potentially relevant neuropathogenic mechanisms 'downstream' of PrPC/PrPSc processes, involving the unfolded protein response (UPR), a compensatory protective cellular mechanism that is stimulated by accumulating levels of misfolded proteins.[88,89] In brief, increasing levels of misfolded proteins initiates a variety of signaling cascades including the UPR.[88,89] Misfolded PrP accumulation leads to an overstimulation a particular branch of the UPR that controls protein synthesis causing a 'transient shutdown' of protein synthesis. This protective mechanism is mediated by the phosphorylation and, therefore, activation of PERK. The activated PERK then induces phosphorylation and activation of eIF2α, which inhibits initiation of translation and effectively terminates the synthesis of cellular proteins, including synaptic proteins. Restoration of protein synthesis occurs via a feedback loop where dephosphorylation of eIF2α is triggered by its specific phosphatase GADD34. Moreno et al. demonstrated that accumulation of misfolded proteins in the brains of prion-infected mice resulted in an unopposed and 'persistent translational repression' of protein synthesis via upregulation of the eIF2α and PERK pathway. The loss of key synaptic proteins subsequently led to synaptic failure and neuronal death.[88] Following on from this, they exploited this pathway by genetically manipulating it upstream and downstream of eIF2α in prion-infected mice. The overall effect was a reduction in activated eIF2α and therefore restoration of translation with recovery of synaptic protein levels. This localized neuroprotection resulted in increased survival times in the prion diseased mice and led the authors to conclude that the inhibition of this pathway offered a potential therapeutic target. In further work, they demonstrated that inhibition of PERK in prion-infected mouse models prevented translational repression and thereby clinical disease in mice, both at the preclinical stage and also in established disease where clinical signs were already observed.[89] There are two particular important features of their studies: firstly, the treatment acted 'downstream' of the replication of the abnormal PrP and the therapeutic benefit remained effective despite ongoing accumulation of misfolded PrP; secondly, this UPR pathway may have important implications for other protein misfolding diseases.