Prion protein attenuates excitotoxicity by inhibiting NMDA receptors

Khosravani, Houman; Zhang, Yunfeng; Tsutsui, Shigeki; Hameed, Shahid; Altier, Christophe; Hamid, Jawed; Chen, Lina; Villemaire, Michelle L.; Ali, Zulfiqar; Jirik, Frank R.; Zamponi, Gerald W.

doi:10.1083/jcb.200711002

Cited by 230 publications

(237 citation statements)

References 50 publications

(68 reference statements)

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“…A less likely alternative is that ⌬CR PrP activates a ubiquitously expressed, endogenous ion channel. There is evidence that PrP functionally and physically interacts with certain types of ionotropic glutamate receptors (45) and that neurons from PrP knock-out mice display several kinds of electrophysiological abnormalities (46 -49). However, the nature of the interactions between PrP and endogenous ion channels remains unclear.…”

Section: Discussionmentioning

confidence: 99%

An N-terminal Polybasic Domain and Cell Surface Localization Are Required for Mutant Prion Protein Toxicity

Solomon

Khatri

Biasini

et al. 2011

Journal of Biological Chemistry

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There is evidence that alterations in the normal physiological activity of PrP C contribute to prion-induced neurotoxicity. This mechanism has been difficult to investigate, however, because the normal function of PrP C has remained obscure, and there are no assays available to measure it. We recently reported that cells expressing PrP deleted for residues 105-125 exhibit spontaneous ionic currents and hypersensitivity to certain classes of cationic drugs. Here, we utilize cell culture assays based on these two phenomena to test how changes in PrP sequence and/or cellular localization affect the functional activity of the protein.We report that the toxic activity of ⌬105-125 PrP requires localization to the plasma membrane and depends on the presence of a polybasic amino acid segment at the N terminus of PrP. Several different deletions spanning the central region as well as three disease-associated point mutations also confer toxic activity on PrP. The sequence domains identified in our study are also critical for PrP Sc formation, suggesting that common structural features may govern both the functional activity of PrP C and its conversion to PrP Sc .Prion diseases or transmissible spongiform encephalopathies comprise a group of fatal neurodegenerative disorders in humans and animals that can be sporadic, infectious, or genetic in origin (1, 2). The prion protein (PrP C ) is a membrane-anchored glycoprotein with no widely agreed-upon physiological function, although its ability to convert into a self-propagating isoform (PrP Sc ) is associated with development of prion diseases. PrP C , thus, plays a crucial role in prion pathogenesis as a substrate for generation of PrP Sc , a conclusion that has been demonstrated by the resistance of PrP-null mice to prion infection (3). In addition, however, there is evidence that PrP C is required for delivery of a toxic signal during prion propagation. This is demonstrated by the fact that brain tissue from PrP-null mice grafted into wild-type animals remains healthy despite the presence of copious amounts of PrP Sc from the surrounding host brain (4). Moreover, conditional genetic ablation of neuronal PrP C allows pathological and clinical recovery of prioninfected mice (5). Therefore, prion neurotoxicity is likely due to subversion of normal PrP C function rather than loss of PrP C or gain of PrP Sc activity (6). However, progress in investigating this mechanism has been hampered by a lack of understanding of the physiological role of PrP C and the absence of assays to measure the functional activity of the protein. To address this issue, our laboratory has recently developed two assays that measure toxicity of PrP mutants expressed in cultured cells. The first assay is a drugbased cellular assay (DBCA) 3 that measures cell death resulting from increased accumulation of two classes of drugs that are normally used to select transfected cell lines (aminoglycosides and bleomycin analogues) (7, 8). The second assay utilizes whole-cell patch clamping to measure the la...

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Section: Discussionmentioning

confidence: 99%

An N-terminal Polybasic Domain and Cell Surface Localization Are Required for Mutant Prion Protein Toxicity

Solomon

Khatri

Biasini

et al. 2011

Journal of Biological Chemistry

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“…For example, neurons from PrP-null mice have been reported to display various kinds of electrophysiological abnormalities (52)(53)(54)(55). It has been suggested that PrP C specifically suppresses the activity of a subclass of NMDA-type glutamate receptors based on the demonstration that PrP C physically interacts with the NR2D subunit of these receptors and the fact that neurons from Prn-p Ϫ/Ϫ mice showed enhanced NMDA-evoked currents and were more susceptible to glutamate-induced excitotoxic death (56). Taken together with our observation that WT PrP silences the currents induced by ⌬CR PrP, the available evidence suggests a possible physiological role for PrP C in regulation of several kinds of ion channels.…”

Section: Biophysical Characteristics and Molecular Basis Of ⌬Cr Prp-imentioning

confidence: 99%

Neurotoxic Mutants of the Prion Protein Induce Spontaneous Ionic Currents in Cultured Cells

Solomon

Huettner

Harris

2010

Journal of Biological Chemistry

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The mechanisms by which prions kill neurons and the role of the cellular prion protein in this process are enigmatic. Insight into these questions is provided by the neurodegenerative phenotypes of transgenic mice expressing prion protein (PrP) molecules with deletions of conserved amino acids in the central region. We report here that expression in transfected cells of the most toxic of these PrP deletion mutants (⌬105-125) induces large, spontaneous ionic currents that can be detected by patchclamping techniques. These currents are produced by relatively non-selective, cation-permeable channels or pores in the cell membrane and can be silenced by overexpression of wild-type PrP, as well as by treatment with a sulfated glycosaminoglycan. Similar currents are induced by PrP molecules carrying several different point mutations in the central region that cause familial prion diseases in humans. The ionic currents described here are distinct from those produced in artificial lipid membranes by synthetic peptides derived from the PrP sequence because they are induced by membrane-anchored forms of PrP that are synthesized by cells and that are found in vivo. Our results indicate that the neurotoxicity of some mutant forms of PrP is attributable to enhanced ion channel activity and that wild-type PrP possesses a channel-silencing activity. Drugs that block PrP-associated channels or pores may therefore represent novel therapeutic agents for treatment of patients with prion diseases.

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“…For instance, PrP C has been involved in the inhibition of excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR). 81 It has been hypothesized that this regulation is executed either through direct interaction of PrP C with NMDAR subunits (PrP C co-immunoprecipitates with the NR2D subunit of the NMDAR) or via protein kinases 82 such as the Src tyrosine kinase family member Fyn. 83 Of note, NMDARs localize in lipid raft domains but can also be present in non-raft domains after phosphorylation.…”

Section: 74mentioning

confidence: 99%