Loss of STI 1‐mediated neuronal survival and differentiation in disease‐associated mutations of prion protein

Cellular prion protein (Pr P C ) is widely expressed and displays a variety of well‐described functions in the central nervous system ( CNS ). Mutations of the PRNP gene are known to promote genetic human spongiform encephalopathies, but the components of gain‐ or loss‐of‐function mutations to Pr P C remain a matter for debate. Among the proteins described to interact with Pr P C is Stress‐inducible protein 1 ( STI 1), a co‐chaperonin that is secreted from astrocytes and triggers neuroprotection and neuritogenesis through its interaction with Pr P C . In this work, we evaluated the impact of different Pr P C pathogenic point mutations on signaling pathways induced by the STI 1‐Pr P C interaction. We found that some of the pathogenic mutations evaluated herein induce partial or total disruption of neuritogenesis and neuroprotection mediated by mitogen‐activated protein kinase (M APK )/extracellular signal‐regulated kinases 1 and 2 ( ERK 1/2) and protein kinase A ( PKA ) signaling triggered by STI 1‐Pr P C engagement. A pathogenic mutant Pr P C that lacked both neuroprotection and neuritogenesis activities fail to promote negative dominance upon wild‐type Pr P C . Also, a STI 1‐α7‐nicotinic acetylcholine receptor‐dependent cellular signaling was present in a Pr P C mutant that maintained both neuroprotection and neuritogenesis activities similar to what has been previously observed by wild‐type Pr P C . These results point to a loss‐of‐function mechanism underlying the pathogenicity of Pr P C mutations.