Anterograde axonal transport of chicken cellular prion protein (PrPc) in vivo requires its N-terminal part

2007 ◽  
Vol 85 (12) ◽  
pp. 2567-2579 ◽  
Author(s):  
Rafal Butowt ◽  
Paul Davies ◽  
David R. Brown
Keyword(s):  
Axonal Transport ◽  
Prion Protein ◽  
Cellular Prion Protein ◽  
Terminal Part ◽  
Anterograde Axonal Transport

A novel cellular prion protein isoform present in rapid anterograde axonal transport

Neuroreport ◽  
1999 ◽  
Vol 10 (17) ◽  
pp. 3639-3644 ◽  
Author(s):  
Katia Rodolfo ◽  
Raymonde Hässig ◽  
Kenneth L. Moya ◽  
Yveline Frobert ◽  
Jacques Grassi ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Prion Protein ◽  
Cellular Prion Protein ◽  
Anterograde Axonal Transport ◽  
Protein Isoform

scholarly journals The Carboxyl Terminus of Tegument Protein pUL21 Contributes to Pseudorabies Virus Neuroinvasion

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
Kai Yan ◽  
Jie Liu ◽  
Xiang Guan ◽  
Yi-Xin Yin ◽  
Hui Peng ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Pseudorabies Virus ◽  
Motor Proteins ◽  
Retrograde Transport ◽  
Cytoplasmic Dynein ◽  
Bimolecular Fluorescence Complementation ◽  
Tegument Protein ◽  
Carboxyl Terminus ◽  
Anterograde Axonal Transport

ABSTRACTFollowing its entry into cells, pseudorabies virus (PRV) utilizes microtubules to deliver its nucleocapsid to the nucleus. Previous studies have shown that PRV VP1/2 is an effector of dynein-mediated capsid transport. However, the mechanism of PRV for recruiting microtubule motor proteins for successful neuroinvasion and neurovirulence is not well understood. Here, we provide evidence that PRV pUL21 is an inner tegument protein. We tested its interaction with the cytoplasmic light chains using a bimolecular fluorescence complementation (BiFC) assay and observed that PRV pUL21 interacts with Roadblock-1. This interaction was confirmed by coimmunoprecipitation (co-IP) assays. We also determined the efficiency of retrograde and anterograde axonal transport of PRV strains in explanted neurons using a microfluidic chamber system and investigated pUL21’s contribution to PRV neuroinvasionin vivo. Further data showed that the carboxyl terminus of pUL21 is essential for its interaction with Roadblock-1, and this domain contributes to PRV retrograde axonal transportin vitroandin vivo. Our findings suggest that the carboxyl terminus of pUL21 contributes to PRV neuroinvasion.IMPORTANCEHerpesviruses are a group of DNA viruses that infect both humans and animals. Alphaherpesviruses are distinguished by their ability to establish latent infection in peripheral neurons. After entering neurons, the herpesvirus capsid interacts with cellular motor proteins and undergoes retrograde transport on axon microtubules. This elaborate process is vital to the herpesvirus lifecycle, but the underlying mechanism remains poorly understood. Here, we determined that pUL21 is an inner tegument protein of pseudorabies virus (PRV) and that it interacts with the cytoplasmic dynein light chain Roadblock-1. We also observed that pUL21 promotes retrograde transport of PRV in neuronal cells. Furthermore, our findings confirm that pUL21 contributes to PRV neuroinvasionin vivo. Importantly, the carboxyl terminus of pUL21 is responsible for interaction with Roadblock-1, and this domain contributes to PRV neuroinvasion. This study offers fresh insights into alphaherpesvirus neuroinvasion and the interaction between virus and host during PRV infection.

The cellular prion protein binds copper in vivo

Nature ◽  
10.1038/37783 ◽  
1997 ◽  
Vol 390 (6661) ◽  
pp. 684-687 ◽  
Author(s):  
David R. Brown ◽  
Kefeng Qin ◽  
Jochen W. Herms ◽  
Axel Madlung ◽  
Jean Manson ◽  
...  
Keyword(s):  
Prion Protein ◽  
Cellular Prion Protein

scholarly journals α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies

2018 ◽  
Vol 115 (30) ◽  
pp. 7813-7818 ◽  
Author(s):  
Iryna Prots ◽  
Janina Grosch ◽  
Razvan-Marius Brazdis ◽  
Katrin Simmnacher ◽  
Vanesa Veber ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Disease Patient ◽  
In Vivo Models ◽  
Human Neurons ◽  
Anterograde Axonal Transport ◽  
Axonal Dysfunction ◽  
Underlying Mechanisms ◽  
Human Ipsc

α-Synuclein (α-Syn) aggregation, proceeding from oligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. α-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of α-Syn oligomers to neurite pathology in human neurons and the underlying mechanisms remain unclear. Here, we demonstrate the formation of oligomeric α-Syn intermediates and reduced axonal mitochondrial transport in human neurons derived from induced pluripotent stem cells (iPSC) from a Parkinson’s disease patient carrying an α-Syn gene duplication. We further show that increased levels of α-Syn oligomers disrupt axonal integrity in human neurons. We apply an α-Syn oligomerization model by expressing α-Syn oligomer-forming mutants (E46K and E57K) and wild-type α-Syn in human iPSC-derived neurons. Pronounced α-Syn oligomerization led to impaired anterograde axonal transport of mitochondria, which can be restored by the inhibition of α-Syn oligomer formation. Furthermore, α-Syn oligomers were associated with a subcellular relocation of transport-regulating proteins Miro1, KLC1, and Tau as well as reduced ATP levels, underlying axonal transport deficits. Consequently, reduced axonal density and structural synaptic degeneration were observed in human neurons in the presence of high levels of α-Syn oligomers. Together, increased dosage of α-Syn resulting in α-Syn oligomerization causes axonal transport disruption and energy deficits, leading to synapse loss in human neurons. This study identifies α-Syn oligomers as the critical species triggering early axonal dysfunction in synucleinopathies.

scholarly journals Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7–PSD-95 binding

2011 ◽  
Vol 22 (17) ◽  
pp. 3041-3054 ◽  
Author(s):  
Patricia Carulla ◽  
Ana Bribián ◽  
Alejandra Rangel ◽  
Rosalina Gavín ◽  
Isidro Ferrer ◽  
...  
Keyword(s):  
Prion Protein ◽  
Knockout Mice ◽  
Neuronal Excitability ◽  
Epileptic Seizures ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Glycosyl Phosphatidylinositol

Cellular prion protein (PrPC) is a glycosyl-phosphatidylinositol–anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrPSC) induces transmissible spongiform encephalopathies. In contrast, PrPC has a number of physiological functions in several neural processes. Several lines of evidence implicate PrPC in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrPC has been implicated in the inhibition of N-methyl-d-aspartic acid (NMDA)–mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnpo/oJnk3o/o mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrPC-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrPC with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6–PSD-95 interaction after KA injections was favored by the absence of PrPC. Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrPC against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.

Identification of a novel pathway for the in vivo regulation of fast anterograde axonal transport

2008 ◽  
Vol 81 ◽  
pp. 93-94
Author(s):  
Gerardo Morfini ◽  
G. Szebenyi ◽  
H. Brown ◽  
R. Wray ◽  
H. Reyna ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Anterograde Axonal Transport

scholarly journals Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1421-1434 ◽  
Author(s):  
CLAUDIA P. FIGUEIREDO ◽  
NATALIA C. FERREIRA ◽  
GISELLE F. PASSOS ◽  
ROBSON DA COSTA ◽  
FERNANDA S. NEVES ◽  
...  
Keyword(s):  
Prion Protein ◽  
Aromatic Compounds ◽  
Prion Diseases ◽  
Intraperitoneal Administration ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Toxicological Evaluation ◽  
Spongiform Encephalopathies

An altered form of the cellular prion protein, the PrPScor PrPRes, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrPRes) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski´s rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases.

Anterograde axonal transport of the exogenous cellular isoform of prion protein in the chick visual system

2006 ◽  
Vol 31 (1) ◽  
pp. 97-108 ◽  
Author(s):  
Rafal Butowt ◽  
Salama Abdelraheim ◽  
David R. Brown ◽  
Christopher S. von Bartheld
Keyword(s):  
Visual System ◽  
Axonal Transport ◽  
Prion Protein ◽  
Anterograde Axonal Transport

scholarly journals mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Neng-Wei Hu ◽  
Andrew J. Nicoll ◽  
Dainan Zhang ◽  
Alexandra J. Mably ◽  
Tiernan O’Malley ◽  
...  
Keyword(s):  
Prion Protein ◽  
Amyloid Β ◽  
Cellular Prion Protein ◽  
Long Term Depression ◽  
Mglu5 Receptors

scholarly journals Expression and characterisation of fully posttranslationally modified cellular prion protein in Pichia pastoris

2013 ◽  
Vol 394 (11) ◽  
pp. 1475-1483
Author(s):  
Jendrik Marbach ◽  
Peter Zentis ◽  
Philipp Ellinger ◽  
Henrik Müller ◽  
Eva Birkmann
Keyword(s):  
Plasma Membrane ◽  
Pichia Pastoris ◽  
Prion Protein ◽  
Prion Diseases ◽  
Phosphatidyl Inositol ◽  
Cellular Prion Protein ◽  
Glycosylation Pattern ◽  
Signal Sequences

Abstract Prion diseases are fatal neurodegenerative diseases which occur as sporadic, genetic, and transmissible disorders. A molecular hallmark of prion diseases is the conformational conversion of the host-encoded cellular form of the prion protein (PrPC) into its misfolded pathogenic isoform (PrPSc). PrPSc is the main component of the pathological and infectious prion agent. The study of the conversion mechanism from PrPC to PrPSc is a major field in prion research. PrPC is glycosylated and attached to the plasma membrane via its glycosyl phosphatidyl inositol (GPI)-anchor. In this study we established and characterised the expression of fully posttranslationally modified mammalian Syrian golden hamster PrPC in the yeast Pichia pastoris using native PrPC-specific N- and C-terminal signal sequences. In vivo as well as in vitro-studies demonstrated that the signal sequences controlled posttranslational processing and trafficking of native PrPC, resulting in PrPC localised in the plasma membrane of P. pastoris. In addition, the glycosylation pattern of native PrPC could be confirmed.

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