Proteasomes and ubiquitin are involved in the turnover of the wild-type prion protein

Yedidia, Yifat; Horonchik, Lior; Tzaban, Salit; Yanai, Anat; Taraboulos, Albert

doi:10.1093/emboj/20.19.5383

Cited by 231 publications

(226 citation statements)

References 50 publications

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“…The UPS is involved in the targeted degradation of most short-lived proteins or proteins that fold improperly within the endoplasmic reticulum. Although inhibition of the UPS causes cytosolic PRNP C accumulation, it is unlikely that the degradation of PRNP Sc occurs mainly in the UPS, 35,36 as PRNP Sc aggregates are unable to enter the narrow channel into the proteasome. On the other hand, the UPS has been reported to be impaired in TSEs, 37,38 and it has been demonstrated that both PRNP Sc and aggregated β-sheet-rich recPRNP inhibit the activity of proteasomes.…”

Section: Discussionmentioning

confidence: 99%

FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice

et al. 2013

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Prion diseases are fatal neurodegenerative disorders and no effective treatment has been established to date. in this study, we evaluated the effect of FK506 (tacrolimus), a macrolide that is known to be a mild immunosuppressant, on prion infection, using cell culture and animal models. We found that FK506 markedly reduced the abnormal form of prion protein (PRNP Sc ) in the cell cultures (N2a58 and MG20) infected with Fukuoka-1 prion. The levels of autophagy-related molecules such as Lc3-ii, ATG12-ATG5 and ATG7 were significantly increased in the FK506-treated cells, and resulted in the increased formation of autolysosomes. Upregulation of the autophagy-related molecules was also seen in the brains of FK506-treated mice and the accumulation of PRNP Sc was delayed. The survival periods in mice inoculated with Fukuoka-1 were significantly increased when FK506 was administered from day 20 post-inoculation. These findings provide evidence that FK506 could constitute a novel antiprion drug, capable of enhancing the degradation of PRNP Sc in addition to attenuation of microgliosis and neuroprotection.

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Section: Discussionmentioning

confidence: 99%

FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice

et al. 2013

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“…The cellular environment is likely to play a key role. The host machinery that usually degrades misfolded proteins [210] may eliminate most of the newly converted proteins. Cellular chaperonelike activities might also be involved in the conversion process, as shown in vitro [65, 207].…”

Section: The Conformational Selection Hypothesismentioning

confidence: 99%

Prion agent diversity and species barrier

2008

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-Mammalian prions are the infectious agents responsible for transmissible spongiform encephalopathies (TSE), a group of fatal, neurodegenerative diseases, affecting both domestic animals and humans. The most widely accepted view to date is that these agents lack a nucleic acid genome and consist primarily of PrP Sc , a misfolded, aggregated form of the host-encoded cellular prion protein (PrP C ) that propagates by autocatalytic conversion and accumulates mainly in the brain. The BSE epizooty, allied with the emergence of its human counterpart, variant CJD, has focused much attention on two characteristics that prions share with conventional infectious agents. First, the existence of multiple prion strains that impose, after inoculation in the same host, specific and stable phenotypic traits such as incubation period, molecular pattern of PrP Sc and neuropathology. Prion strains are thought to be enciphered within distinct PrP Sc conformers. Second, a transmission barrier exists that restricts the propagation of prions between different species. Here we discuss the possible situations resulting from the confrontation between species barrier and prion strain diversity, the molecular mechanisms involved and the potential of interspecies transmission of animal prions, including recently discovered forms of TSE in ruminants.prion / strain / misfolding / species barrier / PrP Table of Mammalian prion diseases or transmissible spongiform encephalopathies (TSE) form a group of related, invariably fatal neurodegenerative disorders of both animals and humans. The brain pathology consists of spongiosis, astrocytosis, neuronal loss and neural tissue from affected individuals contains an infectious agent, the prion, setting these diseases apart from other neurodegenerative diseases. Prion replication is thought to involve in essence the self-perpetuating conversion of the host-encoded cellular prion protein (PrP C ) into a misfolded form (PrP Sc ) that tends to aggregate and may be neurotoxic (for reviews [1,157]). Prion replication may also occur in lymphoid tissues but is there poorly if not pathogenic (for review [126], [133]). PrP C is a protein with two variably occupied glycosylation sites. It is attached at the outer of the plasma membrane by a glycosylphosphatidylinositol anchor. Its secondary structure is rich in alpha-helix and the protein is likely to be in a monomeric state in mild detergents. While its precise physiological function has not been assigned, PrP C is essential for prion replication and neurotoxicity to occur [57,129]. Upon infection, PrP C is refolded -without apparent post-translational modification -into beta-sheet -rich PrP Sc , initially in the presence of exogenous PrP Sc and then by an autocatalytic process. It leads to the formation of aggregates, sometimes of amyloid type, that can be differentiated from PrP C because of their partial resistance to protease digestion and of their insolubility into non-denaturing detergents [153]. Proteinase K, the most commonly used protease, di...

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“…Thus far, cytosolic PrP aggregates have been reported only in studies performed in vitro. [25][26][27][28] We performed additional analyses to further characterize the PrP C aggregates in b-cells. All PrP inclusions described in vitro to date were similar to aggresomes.…”

Section: Prp C Aggregation In Islets Is Unique To B-cellsmentioning

confidence: 99%

Pronounced cytosolic aggregation of cellular prion protein in pancreatic β-cells in response to hyperglycemia

Strom¹,

Wang²,

Reimer

et al. 2007

Laboratory Investigation

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Cellular prion protein (PrP C ), an N-linked glycoprotein, is expressed in a variety of tissues, but its functions remain unclear. PrP C is abundantly expressed in the endocrine pancreas, which regulates blood glucose homeostasis. Therefore, we investigated whether the expression of PrP C was altered in islets of Langerhans in a model of spontaneous type 1 diabetes, the diabetes-prone BioBreeding (BBdp) rat and a model of b-cell adaptation to hyperglycemia, the chronic glucose-infused Sprague Dawley rat. Pancreatic sections from animals aged 7-100 days were stained immunohistochemically and evaluated using light, fluorescence and confocal microscopy. PrP C was ubiquitously expressed in all four major endocrine cell types within islets. Surprisingly, cytosolic inclusions containing PrP C were identified exclusively in a subpopulation of insulin-producing b-cells. The inclusions exhibited different molecular characteristics from the PrP aggregates previously described in vitro in neurons. The frequency of b-cells with PrP C inclusions increased with age and was threefold greater in diabetes-prone rats than in controls at 100 days. Cytosolic PrP C expression in b-cells was suppressed whereas the number and size of PrP C inclusions markedly increased in response to hyperglycemia during the first 2 days of continuous glucose infusion in Sprague Dawley rats. In summary, this is the first report describing in vivo cytosolic PrP C aggregation. These unique PrP C inclusions were b-cell specific, more frequent in diabetes-prone animals, and responded to hyperglycemia in glucose-infused Sprague Dawley rats. These data suggest a potential dysfunction in b-cells of diabetes-prone rats, and point to new avenues for the study of diabetes pathogenesis.

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Proteasomes and ubiquitin are involved in the turnover of the wild-type prion protein

Cited by 231 publications

References 50 publications

FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice

FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice

Prion agent diversity and species barrier

Pronounced cytosolic aggregation of cellular prion protein in pancreatic β-cells in response to hyperglycemia

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