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 (STI1), 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 STI1-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 (ERK1/2) and protein kinase A (PKA) signaling triggered by STI1-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 STI1-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.