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PrPC is a glycoprotein capable to interact with several molecules and mediates diverse signaling pathways. Among numerous ligands, laminin (LN) is known to promote neurite outgrowth and memory consolidation, while amyloid‐beta oligomers (Aβo) trigger synaptic dysfunction. In both pathways, mGluR1 is recruited as co‐receptor. The involvement of PrPC/mGluR1 in these opposite functions suggests that this complex is a key element in the regulation of synaptic activity. Considering that sleep‐wake cycle is important for synaptic homeostasis, we aimed to investigate how sleep deprivation affects the expression of PrPC and its ligands, laminin, Aβo, and mGluR1, a multicomplex that can interfere with neuronal plasticity. To address this question, hippocampi of control (CT) and sleep deprived (SD) C57BL/6 mice were collected at two time points of circadian period (13 hr and 21 hr). We observed that sleep deprivation reduced PrPC and mGluR1 levels with higher effect in active state (21 hr). Sleep deprivation also caused accumulation of Aβ peptides in rest period (13 hr), while laminin levels were not affected. In vitro binding assay showed that Aβo can compete with LN for PrPC binding. The influence of Aβo was also observed in neuritogenesis. LN alone promoted longer neurite outgrowth than non‐treated cells in both Prnp+/+ and Prnp0/0 genotypes. Aβo alone did not show any effects, but when added together with LN, it attenuated the effects of LN only in Prnp+/+ cells. Altogether, our findings indicate that sleep deprivation regulates the availability of PrPC and Aβ peptides, and based on our in vitro assays, these alterations induced by sleep deprivation can negatively affect LN–PrPC interaction, which is known to play roles in neuronal plasticity. [ABSTRACT FROM AUTHOR]

Prion protein (PrPc) is a cell surface glycoprotein that is abundantly expressed in nervous system. The elucidation of the PrPc interactome network and its significance on neural physiology is crucial to understanding neurodegenerative events associated with prion and Alzheimer's diseases. PrPc co-opts stress inducible protein 1/alpha7 nicotinic acetylcholine receptor (STI1/α7nAChR) or laminin/Type I metabotropic glutamate receptors (mGluR1/5) to modulate hippocampal neuronal survival and differentiation. However, potential crosstalk between these protein complexes and their role in peripheral neurons has never been addressed. To explore this issue, we investigated PrPc-mediated axonogenesis in peripheral neurons in response to STI1 and Iaminin-γ1 chain-derived peptide (Ln-γ1). STI1 and Ln-γ1 promoted robust axonogenesis in wild-type neurons, whereas no effect was observed in neurons from PrPc-null mice. PrPc binding to Ln- y1 or STI1 led to an increase in intracellular Caz+ levels via distinct mechanisms: STI1 promoted extracellular Ca2+ influx, and Ln-y1 released calcium from intracellular stores. Both effects depend on phospholipase C activation, which is modulated by mGluR1/5 for Ln-γ1, but depends on, C-type transient receptor potential (TRPC) channels rather than cx7nAChR for STI1. Treatment of neurons with suboptimal concentrations of both ligands led to synergistic actions on PrPc-mediated calcium response and axonogenesis. This effect was likely mediated by simultaneous binding of the two ligands to PrPc. These results suggest a role for PrPc as an organizer of diverse multiprotein complexes, triggering specific signaling pathways and promoting axonogenesis In the peripheral nervous system. [ABSTRACT FROM AUTHOR]

Prion protein (PrP(C)) is a cell surface glycoprotein that is abundantly expressed in nervous system. The elucidation of the PrP(C) interactome network and its significance on neural physiology is crucial to understanding neurodegenerative events associated with prion and Alzheimer's diseases. PrP(C) co-opts stress inducible protein 1/alpha7 nicotinic acetylcholine receptor (STI1/α7nAChR) or laminin/Type I metabotropic glutamate receptors (mGluR1/5) to modulate hippocampal neuronal survival and differentiation. However, potential cross-talk between these protein complexes and their role in peripheral neurons has never been addressed. To explore this issue, we investigated PrP(C)-mediated axonogenesis in peripheral neurons in response to STI1 and laminin-γ1 chain-derived peptide (Ln-γ1). STI1 and Ln-γ1 promoted robust axonogenesis in wild-type neurons, whereas no effect was observed in neurons from PrP(C) -null mice. PrP(C) binding to Ln-γ1 or STI1 led to an increase in intracellular Ca(2+) levels via distinct mechanisms: STI1 promoted extracellular Ca(2+) influx, and Ln-γ1 released calcium from intracellular stores. Both effects depend on phospholipase C activation, which is modulated by mGluR1/5 for Ln-γ1, but depends on, C-type transient receptor potential (TRPC) channels rather than α7nAChR for STI1. Treatment of neurons with suboptimal concentrations of both ligands led to synergistic actions on PrP(C)-mediated calcium response and axonogenesis. This effect was likely mediated by simultaneous binding of the two ligands to PrP(C). These results suggest a role for PrP(C) as an organizer of diverse multiprotein complexes, triggering specific signaling pathways and promoting axonogenesis in the peripheral nervous system., (© 2012 International Society for Neurochemistry.)