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

Author(s)

Landemberger, Michele Christine ^[1] ; de Oliveira, Gabriela Pintar ^[1] ; Machado, Cleiton Fagundes ^{[1, 2]} ; Gollob, Kenneth John ^[1] ; Martins, Vilma Regina ^[1]

Affiliation

^[1] AC Camargo Canc Ctr, Int Res Ctr, BR-01508010 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Biochem, BR-05508000 Sao Paulo - Brazil

• Document type: Journal article
• Source: Journal of Neurochemistry; v. 145, n. 5, p. 409-416, JUN 2018.
• Web of Science Citations: 1

Abstract

Cellular prion protein (PrPC) 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 PrPC remain a matter for debate. Among the proteins described to interact with PrPC is Stress-inducible protein 1 (STI1), a co-chaperonin that is secreted from astrocytes and triggers neuroprotection and neuritogenesis through its interaction with PrPC. In this work, we evaluated the impact of different PrPC pathogenic point mutations on signaling pathways induced by the STI1-PrPC 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-PrPC engagement. A pathogenic mutant PrPC that lacked both neuroprotection and neuritogenesis activities fail to promote negative dominance upon wild-type PrPC. Also, a STI1-7-nicotinic acetylcholine receptor-dependent cellular signaling was present in a PrPC mutant that maintained both neuroprotection and neuritogenesis activities similar to what has been previously observed by wild-type PrPC. These results point to a loss-of-function mechanism underlying the pathogenicity of PrPC mutations. (AU)

• FAPESP's process: 13/26097-0 - Analysis of PrPC/STI1 signaling and possible therapeutic role in Amyotrophic Lateral Sclerosis
• Grantee: Gabriela Pintar de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral