Prions: Generation and Spread versus Neurotoxicity [Molecular Bases of Disease]

May 23rd, 2014 by Halliday, M., Radford, H., Mallucci, G. R.

Neurodegenerative diseases are characterised by aggregation of misfolded proteins in the brain. Amongst these disorders are the prion diseases, which are transmissible. In these, the misfiled proteins, "prions", are also the infectious agent. Increasingly, it appears that misfolded proteins in Alzheimers and Parkinsons diseases and the tauopathies also propagate in a "prion-like" manner. But the association between prion formation and spread and neurotoxicity is not clear. Recently, we showed that in prion disease protein misfolding leads to neurodegeneration through dysregulation of generic proteostatic mechanisms, specifically, the unfolded protein response (UPR). Genetic and pharmacological manipulation of the UPR was neuroprotective despite continuing prion replication, hence dissociating this from neurotoxicity. The data have clear implications for treatment across the spectrum of these disorders, targeting pathogenic processes downstream of protein misfolding.