Spongy state (status spongiosus) and inhibition of Na, K-ATPase: A pathogenetic theory

Calandriello, L.; Curini, Roberta; Pennisi, E.; Palladini, Giovanni

doi:10.1016/0306-9877(95)90132-9

Cited by 10 publications

(6 citation statements)

References 35 publications

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“…Such a process could explain the requirement for PrP C for neurotoxicity of oligomeric protein preparations [73] and there is significant evidence pointing to a role for electrophysiological disturbances in the toxicity of prion protein aggregates [74]. We are certainly not the first to suggest a key role for the loss of Na + /K + -ATPase function in TSE diseases [45], [75], [76] but our work is the first to demonstrate that Na + /K + -ATPase is present in SAF and that this protein can mediate misfolding of PrP.…”

Section: Resultsmentioning

confidence: 92%

“…Palladino et al observed that mutations in the Drosophila α-subunit of Na + /K + -ATPase resulted in severe neuronal damage and a marked reduction in lifespan [44]. Previous work by the same group had indicated that inhibition of the Na + /K + -ATPase caused spongiform vacuolation similar to that seen in TSE infections [45]. Furthermore, PrP C has been shown to interact either directly or indirectly with Na + /K + -ATPase by a variety of techniques, including affinity chromatography [42], cross linking in tissue samples [9], [26], [42] and co-immunoprecipitation experiments [8].…”

Section: Resultsmentioning

confidence: 95%

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Na+/K+-ATPase Is Present in Scrapie-Associated Fibrils, Modulates PrP Misfolding In Vitro and Links PrP Function and Dysfunction

Graham

Kurian²,

Agarwal

et al. 2011

PLoS ONE

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Transmissible spongiform encephalopathies are characterised by widespread deposition of fibrillar and/or plaque-like forms of the prion protein. These aggregated forms are produced by misfolding of the normal prion protein, PrPC, to the disease-associated form, PrPSc, through mechanisms that remain elusive but which require either direct or indirect interaction between PrPC and PrPSc isoforms. A wealth of evidence implicates other non-PrP molecules as active participants in the misfolding process, to catalyse and direct the conformational conversion of PrPC or to provide a scaffold ensuring correct alignment of PrPC and PrPSc during conversion. Such molecules may be specific to different scrapie strains to facilitate differential prion protein misfolding. Since molecular cofactors may become integrated into the growing protein fibril during prion conversion, we have investigated the proteins contained in prion disease-specific deposits by shotgun proteomics of scrapie-associated fibrils (SAF) from mice infected with 3 different strains of mouse-passaged scrapie. Concomitant use of negative control preparations allowed us to identify and discount proteins that are enriched non-specifically by the SAF isolation protocol. We found several proteins that co-purified specifically with SAF from infected brains but none of these were reproducibly and demonstrably specific for particular scrapie strains. The α-chain of Na+/K+-ATPase was common to SAF from all 3 strains and we tested the ability of this protein to modulate in vitro misfolding of recombinant PrP. Na+/K+-ATPase enhanced the efficiency of disease-specific conversion of recombinant PrP suggesting that it may act as a molecular cofactor. Consistent with previous results, the same protein inhibited fibrillisation kinetics of recombinant PrP. Since functional interactions between PrPC and Na+/K+-ATPase have previously been reported in astrocytes, our data highlight this molecule as a key link between PrP function, dysfunction and misfolding.

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 95%

Na+/K+-ATPase Is Present in Scrapie-Associated Fibrils, Modulates PrP Misfolding In Vitro and Links PrP Function and Dysfunction

Graham

Kurian²,

Agarwal

et al. 2011

PLoS ONE

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“…function, bipolar mood disorder, and spongiform encephalopathies such as those caused by prion diseases, namely Kuru, Crutzfeld-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome (Herrera et al, 1988;Calandriello et al, 1995;el-Mallakh and Wyatt, 1995;Mynett-Johnson et al, 1998;Mobasheri et al, 2000). Nonetheless, direct mutation of Na ϩ /K ϩ ATPase ␣ subunit genes has not previously been identified as the cause of neural disease or other syndromes in humans.…”

Section: Discussionmentioning

confidence: 99%

Neural Dysfunction and Neurodegeneration inDrosophilaNa⁺/K⁺ATPase Alpha Subunit Mutants

et al. 2003

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The Na+/K+ ATPase asymmetrically distributes sodium and potassium ions across the plasma membrane to generate and maintain the membrane potential in many cell types. Although these pumps have been hypothesized to be involved in various human neurological disorders, including seizures and neurodegeneration, direct genetic evidence has been lacking. Here, we describe novel mutations in the Drosophila gene encoding the alpha (catalytic) subunit of the Na+/K+ ATPase that lead to behavioral abnormalities, reduced life span, and severe neuronal hyperexcitability. These phenotypes parallel the occurrence of extensive, age-dependent neurodegeneration. We have also discovered that the ATPalpha transcripts undergo alternative splicing that substantially increases the diversity of potential proteins. Our data show that maintenance of neuronal viability is dependent on normal sodium pump activity and establish Drosophila as a useful model for investigating the role of the pump in human neurodegenerative and seizure disorders.

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“…Moreover, an additional consequence is a reduced driving force for a variety of Na-coupled coand counter-transport mechanisms, including impairment of Na + /H + exchange and Na + /Ca 2+ exchange, resulting in intracellular acidification and Ca 2+ -overload. These events have been implicated in the pathogenesis of several neurodegenerative disorders, spongiform encephalopathy, and neuronal injury following exposure of neurons to ouabain or non-specific inhibitors of Na/K-ATPase in experimental animals (27,28,29,30,31,32,33).…”

Section: Intracellular Ion Concentrationsmentioning

confidence: 99%

Neuronal function and alpha3 isoform of the Na/K-ATPase

Dobretsov

Stimers²

2005

Front Biosci

157

125

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The Na/K-ATPase is a complex of integral membrane proteins that carries out active transport of sodium and potassium across the cell plasma membrane, and maintains chemical gradients of these ions. The alpha subunit of the Na/K-ATPase has several isoforms that are expressed in a cell type- and tissue-dependent manner. In adult vertebrates, while kidney cells express mostly alpha1, muscle and glial cells -- alpha1 and alpha2, and sperm cells -- alpha1 and alpha4 isoforms of Na/K-ATPase, neurons may express alpha1, alpha2, alpha3 or any combination of these isoforms, and evidence suggests that neuronal type is the determining factor. The functional significance of multiple isoforms of the Na/K-ATPase and their non-uniform expression, and the link between neuron function and expression of a given isoform of the Na/K-ATPase in particular, remains unknown. Several hypotheses on this account were introduced, and in this work we will review the present status of these hypotheses, and their standing in application to recent data on the expression of isoforms of the Na/K-ATPase in the peripheral nervous system of vertebrate animals.

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Spongy state (status spongiosus) and inhibition of Na, K-ATPase: A pathogenetic theory

Cited by 10 publications

References 35 publications

Na+/K+-ATPase Is Present in Scrapie-Associated Fibrils, Modulates PrP Misfolding In Vitro and Links PrP Function and Dysfunction

Na+/K+-ATPase Is Present in Scrapie-Associated Fibrils, Modulates PrP Misfolding In Vitro and Links PrP Function and Dysfunction

Neural Dysfunction and Neurodegeneration inDrosophilaNa⁺/K⁺ATPase Alpha Subunit Mutants

Neuronal function and alpha3 isoform of the Na/K-ATPase

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Spongy state (status spongiosus) and inhibition of Na, K-ATPase: A pathogenetic theory

Cited by 10 publications

References 35 publications

Na+/K+-ATPase Is Present in Scrapie-Associated Fibrils, Modulates PrP Misfolding In Vitro and Links PrP Function and Dysfunction

Na+/K+-ATPase Is Present in Scrapie-Associated Fibrils, Modulates PrP Misfolding In Vitro and Links PrP Function and Dysfunction

Neural Dysfunction and Neurodegeneration inDrosophilaNa+/K+ATPase Alpha Subunit Mutants

Neuronal function and alpha3 isoform of the Na/K-ATPase

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Product

Resources

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Neural Dysfunction and Neurodegeneration inDrosophilaNa⁺/K⁺ATPase Alpha Subunit Mutants