| First Author | Landemberger MC | Year | 2018 |
| Journal | J Neurochem | Volume | 145 |
| Issue | 5 | Pages | 409-416 |
| PubMed ID | 29337365 | Mgi Jnum | J:263223 |
| Mgi Id | MGI:6160114 | Doi | 10.1111/jnc.14305 |
| Citation | Landemberger MC, et al. (2018) Loss of STI1-mediated neuronal survival and differentiation in disease-associated mutations of prion protein. J Neurochem 145(5):409-416 |
| abstractText | 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-alpha7-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. |
