Prions disturb post-Golgi trafficking of membrane proteins

Uchiyama, Kimio; Muramatsu, Naomi; Yano, Masashi; Usui, Takeshi; Miyata, Hironori; Sakaguchi, Suehiro

doi:10.1038/ncomms2873

Cited by 61 publications

(110 citation statements)

References 43 publications

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“…8, 10, 11). The reduction in net PrP C levels defined by our experiments stands in apparent contrast to a redistribution effect in persistently infected cells, in which cell surface PrP is reduced and immunohistochemical signal in a trans-Golgi network subcompartment is increased (42).…”

Section: Discussioncontrasting

confidence: 43%

Prion disease tempo determined by host-dependent substrate reduction

Mays¹,

Kim²,

Haldiman³

et al. 2014

J. Clin. Invest.

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The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrP Sc ), which is derived from its cellular precursor (PrP C ), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrP C and Sho, we inferred that PrP C levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrP C glycosylation and proteolytic processing, net reductions in PrP C occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrP C results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrP Sc in vitro. While PrP C downregulation is not discernible in animals with unusually short incubation periods and high PrP C expression, slowly evolving prion infections exhibit downregulation of the PrP C substrate required for new PrP Sc synthesis and as a receptor for pathogenic signaling. Our data reveal PrP C downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strains.

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Section: Discussioncontrasting

confidence: 43%

Prion disease tempo determined by host-dependent substrate reduction

Mays¹,

Kim²,

Haldiman³

et al. 2014

J. Clin. Invest.

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“…Furthermore, this affects cellular processes such as post-Golgi vesicular trafficking of membrane proteins [48][49][50][51][52]. One potential interpretation of these studies is that loss of MGRN1 function plays a significant role in neurodegenerative diseases, somewhere linked with NEDD4 [111] Melanocortin signaling [19,110] Spongiform neurodegeneration [16] Cellular protein quality control [61,112] α-tubulin [113] Microtubule stability and mitotic spindle orientation [113] Expanded Polyglutamine Proteins [112] Spermatogenesis [114] Male infertility [114] mitochondrial dysfunction, vacuoles formation and oxidative stress via interaction with the components of cellular quality control mechanism as summarized in Table 1.…”

Section: Molecular Functions Of Mgrn1 In Neurodegenerative Diseasesmentioning

confidence: 99%

Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

et al. 2015

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In healthy cell, inappropriate accumulation of poor or damaged proteins is prevented by cellular quality control system. Autophagy and ubiquitin proteasome system (UPS) provides regular cytoprotection against proteotoxicity induced by abnormal or disruptive proteins. E3 ubiquitin ligases are crucial components in this defense mechanism. Mahogunin Ring Finger-1 (MGRN1), an E3 ubiquitin ligase of the Really Interesting New Gene (RING) finger family, plays a pivotal role in many biological and cellular mechanisms. Previous findings indicate that lack of functions of MGRN1 can cause spongiform neurodegeneration, congenital heart defects, abnormal left-right patterning, and mitochondrial dysfunctions in mice brains. However, the detailed molecular pathomechanism of MGRN1 in cellular functions and diseases is not well known. This article comprehensively represents the molecular nature, characterization, and functions of MGRN1; we also summarize possible beneficiary aspects of this novel E3 ubiquitin ligase. Here, we review recent literature on the role of MGRN1 in the neuro-pathobiological mechanisms, with precise focus on the processes of neurodegeneration, and thereby propose new lines of potential targets for therapeutic intervention.

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“…Certainly many reports suggest that normal physiological function is altered during prion infection. For example Uchiyama et al 12 , show that post-Golgi trafficking of other raft-associated membrane proteins is disturbed in prion-infected N2A cells. There is also increased signaling activity such as from Src kinases.…”

Section: Prp C Levels Affect Tnt Formationmentioning

confidence: 99%

“…On the other hand, numerous studies show that, in infected cells, a large percentage of PrP Sc is found internally, along the endocytic and secretory pathways. 1,11,12 Furthermore, we have demonstrated that the endocytic recycling compartment (ERC) is a major intracellular site of PrP Sc conversion. 13 Thus, a likely possibility is that the TNTmediated prion transfer occurs using active transport of prion-containing vesicles.…”

Section: Introductionmentioning

confidence: 99%

Prion aggregates transfer through tunneling nanotubes in endocytic vesicles

Zhu

Victoria

Marzo

et al. 2015

Prion

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ABSTRACT. Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases caused by the misfolding of the cellular prion protein to an infectious form PrP Sc . The intercellular transfer of PrP Sc is a question of immediate interest as the cell-to-cell movement of the infectious particle causes the inexorable propagation of disease. We have previously identified tunneling nanotubes (TNTs) as one mechanism by which PrP Sc can move between cells. Here we investigate further the details of this mechanism and show that PrP Sc travels within TNTs in endolysosomal vesicles. Additionally we show that prion infection of CAD cells increases both the number of TNTs and intercellular transfer of membranous vesicles, thereby possibly playing an active role in its own intercellular transfer via TNTs.

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Prions disturb post-Golgi trafficking of membrane proteins

Cited by 61 publications

References 43 publications

Prion disease tempo determined by host-dependent substrate reduction

Prion disease tempo determined by host-dependent substrate reduction

Mahogunin Ring Finger-1 (MGRN1), a Multifaceted Ubiquitin Ligase: Recent Unraveling of Neurobiological Mechanisms

Prion aggregates transfer through tunneling nanotubes in endocytic vesicles

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