by Keyword: PrPC
Urrea, Laura, Ferrer, Isidro, Gavín, Rosalina, del Río, José Antonio, (2017). The cellular prion protein (PrPC) as neuronal receptor for α-synuclein Prion , 11, (4), 226-233
The term ‘prion-like’ is used to define some misfolded protein species that propagate intercellularly, triggering protein aggregation in recipient cells. For cell binding, both direct plasma membrane interaction and membrane receptors have been described for particular amyloids. In this respect, emerging evidence demonstrates that several β-sheet enriched proteins can bind to the cellular prion protein (PrPC). Among other interactions, the physiological relevance of the binding between β-amyloid and PrPC has been a relevant focus of numerous studies. At the molecular level, published data point to the second charged cluster domain of the PrPC molecule as the relevant binding domain of the β-amyloid/PrPC interaction. In addition to β-amyloid, participation of PrPC in binding α-synuclein, responsible for neurodegenerative synucleopathies, has been reported. Although results indicate relevant participation of PrPC in the spreading of α-synuclein in living mice, the physiological relevance of the interaction remains elusive. In this comment, we focus our attention on summarizing current knowledge of PrPC as a receptor for amyloid proteins and its physiological significance, with particular focus on α-synuclein.
JTD Keywords: α-synuclein, Charged cluster domain, Interneuronal transport, LAG3, Neurodegeneration, PrPC, Parkinson disease
Rangel, A., Madroñal, N., Gruart i Massó, A., Gavin,, Llorens, Sumoy, Torres, Delgado-Gar, Del Rio, J. A., (2009). Regulation of GABA(A) and glutamate receptor expression, synaptic facilitation and long-term potentiation in the hippocampus of prion mutant mice PLoS ONE 4, (10), e7592 (1-14)
Background: Prionopathies are characterized by spongiform brain degeneration, myoclonia, dementia, and periodic electroencephalographic (EEG) disturbances. The hallmark of prioniopathies is the presence of an abnormal conformational isoform (PrPsc) of the natural cellular prion protein (PrPc) encoded by the Prnp gene. Although several roles have been attributed to PrPc, its putative functions in neuronal excitability are unknown. Although early studies of the behavior of Prnp knockout mice described minor changes, later studies report altered behavior. To date, most functional PrPc studies on synaptic plasticity have been performed in vitro. To our knowledge, only one electrophysiological study has been performed in vivo in anesthetized mice, by Curtis and coworkers. They reported no significant differences in paired-pulse facilitation or LTP in the CA1 region after Schaffer collateral/commissural pathway stimulation. Methodology/Principal Findings: Here we explore the role of PrPc expression in neurotransmission and neural excitability using wild-type, Prnp 2/2 and PrPc-overexpressing mice (Tg20 strain). By correlating histopathology with electrophysiology in living behaving mice, we demonstrate that both Prnp 2/2 mice but, more relevantly Tg20 mice show increased susceptibility to KA, leading to significant cell death in the hippocampus. This finding correlates with enhanced synaptic facilitation in paired-pulse experiments and hippocampal LTP in living behaving mutant mice. Gene expression profiling using IlluminaTM microarrays and Ingenuity pathways analysis showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission were co-regulated in Prnp 2/2 and Tg20 mice. Lastly, RT-qPCR of neurotransmission-related genes indicated that subunits of GABAA and AMPA-kainate receptors are co-regulated in both Prnp 2/2 and Tg20 mice. Conclusions/Significance: Present results demonstrate that PrPc is necessary for the proper homeostatic functioning of hippocampal circuits, because of its relationships with GABAA and AMPA-Kainate neurotransmission. New PrPc functions have recently been described, which point to PrPc as a target for putative therapies in Alzheimer’s disease. However, our results indicate that a ‘‘gain of function’’ strategy in Alzheimer’s disease, or a ‘‘loss of function’’ in prionopathies, may impair PrPc function, with devastating effects. In conclusion, we believe that present data should be taken into account in the development of future therapies.
JTD Keywords: Prions, Prionopathies, Natural cellular prion protein (PrPc), Hippocampus, GABA (A) receptor, Glutamate Receptor