Special Issue "Recent Developments in the Prion Field"

Guest Editor
Prof. Dr. Judd Aiken
Centre for Prions and Protein Folding Diseases, AFNS, University of Alberta, Edmonton, Alberta, T6G 2M8, Canada
Website: http://www.prioncentre.ca/people/aiken.php
E-Mail: jmaiken@ualberta.ca
Phone: +780 492 9377
Fax: +780 492 9352

Guest Editor
Prof. Dr. Debbie McKenzie
Centre for Prions and Protein Folding Diseases, AFNS, University of Alberta, Edmonton, Alberta, T6G 2M8, Canada
Website: http://www.prioncentre.ca/people/mckenzie.php
E-Mail: debbie.mckenzie@ualberta.ca
Phone: +780 492 9377
Fax: +780 492 9352

Submission

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Type of Paper: Article
Title: Prions, the Amyloid Precursor Protein and Alzheimer's Disease; Convergent Molecular Pathways and Pathogenic Mechanisms
Author: Edward T. Parkin
Affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK.
Abstract: Prion diseases and Alzheimer's disease (AD) are examples of neurodegenerative amyloidoses which, until recently, were considered mutually exclusive, with the prion protein (PrP) and the amyloid precursor protein (APP), respectively, giving rise to the neurotoxic protein/peptide aggregates characteristic of the two conditions. However, the possible involvement of prions in the molecular mechanisms key to the development of AD has now become a hotly debated topic. Various groups have generated seemingly contradictory data on whether PrP might be protective against AD or, conversely, might be an essential agent in the molecular mechanisms promoting the condition. Regardless of such conflicts, it is clear that PrP and APP have much in common in terms of both functionality and cell biology. The current article reviews the convergent molecular pathways involved in the cell biology of the two proteins and the possible interplay between PrP and APP in the pathogenesis of Alzheimer's disease.

Type of Paper: Communication
Title: Expression of GPI-anchorless Splice Variant of the Prion Protein in Human Brain
Authors: Yutaka Kikuchi ^1,*, Toshie Kanayasu-Toyoda ², Osamu Nakajima ³, Reiko Teshima ³, Yoshiko Sugita-Konishi ¹ and Teruhide Yamaguchi ²
Affiliations: ¹ Division of Microbiology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; E-Mails: kikuchi@nihs.go.jp (Y.K); ykonishi@nihs.go.jp (Y.S.-K.)
² Division of Biological chemistry and Biologicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; E-Mails: ttoyoda@nihs.go.jp (T.K.-T.); yamaguch@nihs.go.jp (T.Y.)
³ Division of Novel Foods and Immunochemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; E-Mails:  onakajim@nihs.go.jp (O.N.); rteshima@nihs.go.jp (R.T.)
* Author to whom correspondence should be addressed; E-Mail: kikuchi@nihs.go.jp (Y.K.); Tel.: +81-3-3700-1141; Fax: +81-3-3707-6950.
Abstract:  The human prion protein (PrP) is a glycoprotein with a glycosylphosphatidylinositol (GPI) anchor at its C-terminus.  Alternative splicing of PrP mRNAs where the coding region of the PrP exon is not involved has been described in cattle, mice and sheep.  Variant forms of human PrP arising from alternative mRNA splicing within exon2 of the PrP gene (PRNP) had not been reported.  Recently, we reported alternative splicing within exon 2 of the PRNP in the human glioblastoma cell line T98G.  The open reading frame of the alternatively spliced mRNA lacked the GPI anchor signal sequence and encoded a 230 amino acid polypeptide.  Its product, GPI-anchorless PrP (GPI¯PrPSV), was unglycosylated and soluble in non-ionic detergent, and was found in the cytosolic fraction.  When T98G cells were placed in a low-oxygen environment, alternatively spliced mRNA expression increased and expression of normally spliced PrP mRNA decreased.  These findings imply that oxygen tension regulates GPI¯PrPSV expression in T98G cells.  We also detected alternatively spliced mRNA in human brain and non-neuronal tissues.  It will be important to understand how oxygen tension regulates GPI¯PrPSV expression, and its relationship with the expression level of GPI¯PrPSV and prion diseases requires further investigation.
Keywords: prion; alternative splicing; GPI anchor

Type of Paper: Review
Title: Towards the Cellular Mechanisms of Propagation and Clearance of Prions
Authors: Hermann M. Schatzl
Affiliation: Wyoming Excellence Chair in Prion Biology, Departments of Molecular Biology and Veterinary Sciences, University of Wyoming, Laramie 82071, Wyoming, USA.
Abstract: Prion diseases are infectious fatal neurodegenerative disorders of man and animals which are characterized by
spongiform degeneration in the CNS. A hallmark is the accumulation of a misfolded and pathologic isoform (PrP^Sc) of the host-encoded normal prion protein (PrP^c). Understanding the precise mechanisms of prion conversion on a cellular level and how cells can react and counteract are crucial for devising drugs effectively targeting these diseases. We have extensively characterized intracellular aggregation, trafficking and degradation of prion proteins in prion-infected cells in recent years. Here, we focus on implications of two major cellular degradation pathways on prion replication and clearance. The first one is autophagy which we think can have a promoting and inhibiting role in prion infection. We have shown that prion clearance can be enhanced in vitro and in vivo by drug-induced activation of autophagy. We have analyzed chemical drugs known to induce autophagy and using siRNA approaches we demonstrated that induction of autophagy is the underlying mechanism for increased lysosomal clearance of prions. More recent work using cells compromised in autophagy has revealed that a certain level of autophagy is needed for establishing acute and persistent prion infection. We speculate that autophagy might represent a functional equivalent for a disaggregase function, which is postulated for seed fragmentation in prion propagation, similar to sonication in PMCA or Hsp104 in yeast prion biology. Taken together, there seems to be a fascinating interplay between prion infections and autophagy. The second pathway we are interested in is the proteasomal one. We challenged different cell lines by inducing ER-stress or inhibiting proteasomal activity and analyzed the subsequent repercussion on PrP metabolism, focusing strictly on PrP in the secretory pathway. Both events led to enhanced detection of PrP aggregates and significant increase of PrP^Sc in persistently prion-infected cells, which could be reversed by over-expression of proteins of the cellular quality control. Remarkably, upon proteasomal impairment, an increased fraction of misfolded, fully glycosylated PrP molecules travelled through the secretory pathway and reached the plasma membrane. These findings suggest a novel pathway which possibly provides additional substrate and template for prion formation when protein clearance by the proteasome is impaired. Overall, these studies add to the understanding of the molecular requirements for cellular prion propagation and point to mechanisms which also might play a role in prion de novo generation as relevant in sporadic prion diseases.