Loss of STI1‐mediated neuronal survival and differentiation in disease‐associated mutations of prion protein

Cellular prion protein (PrP^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 PrP^C remain a matter for debate. Among the proteins described to interact with PrP^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 PrP^C . In this work, we evaluated the impact of different PrP^C pathogenic point mutations on signaling pathways induced by the STI 1‐PrP^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 (MAPK )/extracellular signal‐regulated kinases 1 and 2 (ERK 1/2) and protein kinase A (PKA ) signaling triggered by STI 1‐PrP^C engagement. A pathogenic mutant PrP^C that lacked both neuroprotection and neuritogenesis activities fail to promote negative dominance upon wild‐type PrP^C . Also, a STI 1‐α7‐nicotinic acetylcholine receptor‐dependent cellular signaling was present in a PrP^C mutant that maintained both neuroprotection and neuritogenesis activities similar to what has been previously observed by wild‐type PrP^C . These results point to a loss‐of‐function mechanism underlying the pathogenicity of PrP^C mutations.