. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med. 2013 Oct 9;5(206):206ra138. PubMed.

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  1. This is a very interesting and exhaustive study. The authors checked several doses of the PERK kinase inhibitor and its ability to cross the blood-brain barrier. They analyzed the effect on unfolded protein response (UPR) markers, neuronal loss, and gliosis, as well as neuropathological and clinical alterations. For all the parameters that were monitored (except accumulation of prion protein), the kinase inhibitor showed a very robust and impressive effect, even when added after behavioral signs had emerged.

    Since the PERK-mediated UPR branch has been implicated in numerous other neurodegenerative diseases, a kinase inhibitor that crosses the blood-brain barrier and is able to rescue several pathological features that are common to these disorders seems a very promising therapeutic strategy. In addition, the biological activity observed at late disease stages is very encouraging. My only concerns are that this inhibitor does not affect prion protein accumulation and, therefore, long-term administration may induce accumulation of prion protein levels that become neurotoxic through PERK-independent pathways. Also, more information is needed regarding the inhibitor’s toxicity in the liver, kidney, and other organs.