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These authors contributed equally to this study.Abbreviations used: 3-MA, 3-methyladenine; FACS, fluorescenceactivated cell sorting; GFP, green fluorescent protein; LC3, microtubuleassociated protein 1 light chain 3; MEF, mouse embryonic fibroblasts; mTOR, mammalian target of rapamycin; PrP, prion protein; PrP AbstractLithium is used for several decades to treat manic-depressive illness (bipolar affective disorder). Recently, it was found that lithium induces autophagy, thereby promoting the clearance of mutant huntingtin and a-synucleins in experimental systems. We show here for the first time that lithium significantly reduces the amount of pathological prion protein (PrP Sc ) in

A conformational transition of the cellular prion protein (PrP(C)) into an aberrantly folded isoform designated scrapie prion protein (PrP(Sc)) is the hallmark of a variety of neurodegenerative disorders collectively called prion diseases. They include Creutzfeldt-Jakob disease and Gerstmann-Stäussler-Scheinker syndrome in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in free-ranging deer. In contrast to the deadly properties of misfolded PrP, PrP(C) seems to possess a neuroprotective activity. More-over, animal models indicated that the stress-protective activity of PrP(C) and the neurotoxic effects of PrP(Sc) are somehow interconnected.In this timely book, leading scientists in the field have come together to highlight the apparently incongruous activities of different PrP conformers. The articles outline current research on celluar pathways implicated in the formation and signaling of neurotoxic and physiological PrP isoforms and delineate future research direction. Topics covered include the physiologcial activity of PrP(C) and its possible role as a neurotrophic factor, the finding that aberrant PrP conformers can cause neurodegeneration in the absence of infectious prion propagation, the requirement of the GPI anchor of PrP(C) for the neurotoxic effects of scrapie prions, the pathways implicated in the formation and neurotoxic properties of cytosolically localized PrP, the impact of metal ions on the processing of PrP, and the role of autophagy in the propagation and clearance of PrP(Sc). The book is fully illustrated and chapters include comprehensive reference sections.Essential reading for scientists involved in prion research.

The cellular prion protein (PrP c ) is a glycosyl-phosphatidylinositol (GPI)-anchored protein trafficking in the secretory and endocytic pathway and localized mainly at the plasma membrane. Conversion of PrP c into its pathogenic isoform PrP Sc is associated with pathogenesis and transmission of prion diseases. Intramolecular cleavage in the middle, the extreme C-terminal part or within the GPI anchor and shedding of PrP c modulate this conversion process by reducing the substrate for prion formation. These phenomena provide similarities with the processing of amyloid precursor protein in Alzheimer's disease. Sorting nexins are a family of proteins with important functions in protein trafficking. In this study, we investigated the role of the newly described sorting nexin 33 (SNX33) in trafficking and processing of PrP c . We found that overexpression of SNX33 in neuronal and nonneuronal cell lines resulted in increased shedding of fulllength PrP c from the plasma membrane and modulated the rate of PrP c endocytosis. This was paralleled by reduction of PrP Sc formation in persistently and newly infected cells. Using deletion mutants, we demonstrate that production of PrP fragment N1 is not influenced by SNX33. Our data provide new insights into the cellular mechanisms of PrP c shedding and show how this can affect cellular PrP Sc conversion.

Prion diseases are infectious and fatal neurodegenerative disorders of man and animals which are characterized by spongiform degeneration in the central nervous system. Prion propagation involves the endocytic pathway and endosomal and lysosomal compartments are implicated in trafficking and re-cycling as well as final degradation of prions. Shifting the equilibrium between propagation and lysosomal clearance to the latter impairs cellular prion load. This and earlier findings of autophagic vacuoles in correlation to prion infections both in in vitro and in vivo studies prompted us and others to analyze the role of autophagy in prion infection. Autophagy is a fundamental cellular bulk degradation process for e.g. organelles or cytoplasmic proteins which has many implications for physiology and patho-physiology of cells and whole organisms. In various neurodegenerative disease models mainly protective functions of autophagy were recently described. In this review, we focus on recent findings which correlate autophagy and its manipulations with prion infection scenarios, and discuss perspectives and future directions. The findings summarized here add to the knowledge of the role of autophagy in neurodegeneration and provide interesting new insight into how non-cytosolic aggregated proteins might be subjected to autophagic clearance.