Table of Contents

Volume 3, Issue 2

  April/May/June 2009

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 Issue Catalogue (MARC XML)

REVIEWS

Open Access Article

Molecular chaperones antagonize proteotoxicity by differentially modulating protein aggregation pathways

Peter M. Douglas, Daniel W. Summers and Douglas M. Cyr
Pages 51 - 58
http://dx.doi.org/10.4161/pri.3.2.8587
Abstract | PDF

The self-association of misfolded or damaged proteins into ordered amyloid-like aggregates characterizes numerous neurodegenerative disorders.  Insoluble amyloid plaques are diagnostic of many disease states.  Yet soluble, oligomeric intermediates in the aggregation pathway appear to represent the toxic culprit.  Molecular chaperones regulate the fate of misfolded proteins and thereby influence their aggregation state.  Chaperones conventionally antagonize aggregation of misfolded, disease proteins and assist in refolding or degradation pathways.  Recent work suggests that chaperones may also suppress neurotoxicity by converting toxic, soluble oligomers into benign aggregates.  Chaperones can therefore suppress or promote aggregation of disease proteins to ameliorate the proteotoxic accumulation of soluble, assembly intermediates.

Open Access Article

Prion propagation by Hsp40 molecular chaperones

Daniel W. Summers, Peter M. Douglas and Douglas M. Cyr
Pages 59 - 64
http://dx.doi.org/10.4161/pri.3.2.9062
Abstract | PDF

Molecular chaperones regulate essential steps in the propagation of yeast prions. Yeast prions possess domains enriched in glutamines and asparagines that act as templates to drive the assembly of native proteins into beta-sheet-rich, amyloid-like fibrils. Several recent studies highlight a significant and complex function for Hsp40 co-chaperones in propagation of prion elements in yeast. Hsp40 co-chaperones bind non-native polypeptides and transfer these clients to Hsp70s for refolding or degradation. How Hsp40 co-chaperones bind amyloid-like prion conformers that are enriched in hydrophilic residues such as glutamines and asparagines is a significant question in the field. Interestingly, selective recognition of amyloid-like conformers by distinct Hsp40s appears to confer opposing actions on prion assembly. For example, the Type I Hsp40 Ydj1 and Type II Hsp40 Sis1 bind different regions within the prion protein Rnq1 and function respectively to inhibit or promote [RNQ⁺] prion assembly. Thus, substrate selectivity enables distinct Hsp40s to act at unique steps in prion propagation.

Open Access Article

Influence of Hsp70s and their regulators on yeast prion propagation

Daniel C. Masison, P. Aaron Kirkland and Deepak Sharma
Pages 65 - 73
http://dx.doi.org/10.4161/pri.3.2.9134
Abstract | PDF

Propagation of yeast prions requires normal abundance and activity of many protein chaperones. Central among them is Hsp70, a ubiquitous and essential chaperone involved in many diverse cellular processes that helps promote proper protein folding and acts as a critical component of several chaperone machines. Hsp70 is regulated by a large cohort of co-chaperones, whose effects on prions are likely mediated through Hsp70. Hsp104 is another chaperone, absent from mammalian cells, that resolubilizes proteins from aggregates. This activity, which minimally requires Hsp70 and its co-chaperone Hsp40, is essential for yeast prion replication. Although much is known about how yeast prions can be affected by altering protein chaperones, mechanistic explanations for these effects are uncertain. We discuss the variety of effects Hsp70 and its regulators have on different prions and how the effects might be due to the many ways chaperones interact with each other and with amyloid.




COMMENTARIES & VIEWS

Open Access Article

The expanding realm of prion phenomena in neurodegenerative disease

Bess Frost and Marc I. Diamond
Pages 74 - 77
http://dx.doi.org/10.4161/pri.3.2.8754
Abstract | PDF

The aggregation of a soluble protein into insoluble, β-sheet rich amyloid fibrils is a defining characteristic of many neurodegenerative diseases, including prion disorders.  The prion protein has so far been considered unique because of its infectious nature.  Recent investigations, however, suggest that other amyloid-forming proteins associated with much more common diseases, such as tau, α-synuclein, amyloid β, and polyglutamine proteins, while not infectious in the classical sense, share certain essential properties with prions that may explain phenotypic diversity, and patterns of spread within the nervous system. We suggest a common mechanism of pathogenesis of myriad sporadic and inherited neurodegenerative diseases based on templated conformational change.

Open Access Article

Minocycline as a potential therapeutic agent in neurodegenerative disorders characterized by protein misfolding

Wendy Noble, Claire J. Garwood and Diane P. Hanger
Pages 78 - 83
http://dx.doi.org/10.4161/pri.3.2.8820
Abstract | PDF

Many neurodegenerative disorders share common features including the accumulation of aggregated misfolded proteins, neuroinflammation and apoptotic neuronal death. While the contributions of each of these individual elements to neuronal death remain unclear, a commonly used antibiotic, minocycline, has been shown to reduce the progression and severity of disease in several models of neurodegeneration by variously downregulating these molecular pathways. Here we discuss the evidence for the potential of minocycline as a broad-specificity therapeutic agent for those neurodegenerative diseases that are characterised by the presence of misfolded proteins.

Open Access Article

The centrosome and asymmetric cell division

Yukiko M. Yamashita
Pages 84 - 88
http://dx.doi.org/10.4161/pri.3.2.8821
Abstract | PDF

Asymmetric stem cell division is a mechanism widely employed by the cell to maintain tissue homeostasis, resulting in the production of one stem cell and one differentiating cell.  However, asymmetric cell division is not limited to stem cells and is widely observed even in unicellular organisms as well as in cells that make up highly complex tissues.  In asymmetric cell division, cells must organize their intracellular components along the axis of asymmetry(sometimes in the context of extracellular architecture).  Recent studies have described cell asymmetry in many cell types, and in many cases such asymmetry involves the centrosome (or spindle pole body in yeast) as the center of cytoskeleton organization.  In this review, I summarize recent discoveries in cellular polarity that lead to an asymmetric outcome, with a focus on centrosome function.

Open Access Article

Structural polymorphism of Alzheimer Aβ and other amyloid fibrils

Marcus Fändrich, Jessica Meinhardt and Nikolaus Grigorieff
Pages 89 - 93
http://dx.doi.org/10.4161/pri.3.2.8859
Abstract | PDF

Deposits of amyloid fibrils characterize a diverse group of human diseases that includes Alzheimer’s disease, Creutzfeldt-Jakob disease and type II diabetes. Amyloid fibrils formed from different polypeptides contain a common cross-β spine. Nevertheless, amyloid fibrils formed from the same polypeptide can occur in a range of structurally different morphologies. The heterogeneity of amyloid fibrils reflects different types of polymorphism: (i) variations in the protofilament number, (ii) variations in the protofilament arrangement and (iii) different polypeptide conformations. Amyloid fibril polymorphism implies that fibril formation can lead, for the same polypeptide sequence, to many different patterns of inter- or intra-residue interactions. This property differs significantly from native, monomeric protein folding reactions that produce, for one protein sequence, only one ordered conformation and only one set of inter-residue interactions.

Open Access Article

Tunnelling nanotubes: A highway for prion spreading?

Karine Gousset and Chiara Zurzolo
Pages 94 - 98
http://dx.doi.org/10.4161/pri.3.2.8917
Abstract | PDF

The discovery of tunnelling nanotubes (TNTs) and their proposed role in long intercellular transport of organelles, bacteria, and viruses have led us to examine their potential role during prion spreading.  We have recently shown that these membrane bridges can form between neuronal cells, as well as between dendritic cells and primary neurons and that both endogenous and exogenous PrP^Sc appear to traffic through these structures between infected and non-infected cells.  Furthermore, prion infection can be efficiently transmitted from infected dendritic cells to primary neurons only in co-culture conditions permissive for TNT formation.  Therefore, we propose a role for TNTs during prion spreading from the periphery to the central nervous system (CNS).  Here, we discuss some of the key steps where TNTs might play a role during prion neuroinvasion.




RESEARCH PAPERS

Open Access Article

Comparative prion disease gene expression profiling using the prion disease mimetic, cuprizone

Laura R. Moody, Allen J. Herbst, Han Sang Yoo, Joshua P. Vanderloo and Judd M. Aiken
Pages 99 - 109
http://dx.doi.org/10.4161/pri.3.2.9059
Abstract | PDF

Identification of genes expressed in response to prion infection may elucidate biomarkers for disease, identify factors involved in agent replication, mechanisms of neuropathology and therapeutic targets.  Although several groups have sought to identify gene expression changes specific to prion disease, expression profiles rife with cell population changes have consistently been identified.  Cuprizone, a neurotoxicant, qualitatively mimics the cell population changes observed in prion disease, resulting in both spongiform change and astrocytosis.  The use of cuprizone-treated animals as an experimental control during comparative expression profiling allows for the identification of transcripts whose expression increases during prion disease and remains unchanged during cuprizone-triggered neuropathology.  In this study, expression profiles from the brains of mice preclinically and clinically infected with Rocky Mountain Laboratory (RML) mouse-adapted scrapie agent and age-matched controls were profiled using Affymetrix gene arrays.  In total, 164 genes were differentially regulated during prion infection.  Eighty-three of these transcripts have been previously undescribed as differentially regulated during prion disease.  A 0.4% cuprizone diet was utilized as a control for comparative expression profiling.  Cuprizone treatment induced spongiosis and astrocyte proliferation as indicated by glial fibrillary acidic protein (Gfap) transcriptional activation and immunohistochemistry.  Gene expression profiles from brain tissue obtained from cuprizone-treated mice identified 307 differentially regulated transcript changes.  After comparative analysis, 17 transcripts unaffected by cuprizone treatment but increasing in expression from preclinical to clinical prion infection were identified.  Here we describe the novel use of the prion disease mimetic, cuprizone, to control for cell population changes in the brain during prion infection.

Open Access Article

The cellular prion protein and its role in Alzheimer disease

J. L. Velayos, A. Irujo, M. Cuadrado, B. Paternain, F. J. Moleres and V. Ferrer
Pages 110 - 117
http://dx.doi.org/10.4161/pri.3.2.9135
Abstract | PDF

The cellular prion protein (PrP^C) is a membrane-bound glycoprotein especially abundant in the central nervous system (CNS). The scrapie prion protein (PrP^Sc, also termed prions) is responsible of transmissible spongiform encephalopathies (TSE), a group of neurodegenerative diseases which affect humans and other mammal species, although the presence of PrP^C is needed for the establishment and further evolution of prions. The present work compares the expression and localization of PrP^C between healthy human brains and those suffering from Alzheimer’s disease (AD). In both situations we have observed a rostrocaudal decrease in the amount of PrP^C within the CNS, both by immunoblotting and immunohistochemistry techniques. PrP^C is higher expressed in our control brains than in AD cases. There was a neuronal loss and astogliosis in our AD cases. There was a tendency of a lesser expression of PrP^C in AD cases than in healthy ones. And in AD cases, the intensity of the expression of the unglycosylated band is higher than the di- and monoglycosylated bands. With regards to amyloid plaques, those present in AD cases were positively labeled for PrP^C, a result which is further supported by the presence of PrP^C in the amyloid plaques of a transgenic line of mice mimicking AD. The work was done according to Helsinki Declaration of 1975 and approved by the Ethics Committee of the Faculty of Medicine of the University of Navarre.