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      Deficiency of prion protein induces impaired autophagic flux in neurons

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          Abstract

          Normal cellular prion protein (PrP C) is highly expressed in the central nervous system. The Zürich I Prnp-deficient mouse strain did not show an abnormal phenotype in initial studies, however, in later studies, deficits in exploratory behavior and short- and long-term memory have been revealed. In the present study, numerous autophagic vacuoles were found in neurons from Zürich I Prnp-deficient mice. The autophagic accumulation in the soma of cortical neurons in Zürich I Prnp-deficient mice was observed as early as 3 months of age, and in the hippocampal neurons at 6 months of age. Specifically, there is accumulation of electron dense pigments associated with autophagy in the neurons of Zürich I Prnp-deficient mice. Furthermore, autophagic accumulations were observed as early as 3 months of age in the CA3 region of hippocampal and cerebral cortical neuropils. The autophagic vacuoles increased with age in the hippocampus of Zürich I Prnp-deficient mice at a faster rate and to a greater extent than in normal C57BL/6J mice, whereas the cortex exhibited high levels that were maintained from 3 months old in Zürich I Prnp-deficient mice. The pigmented autophagic accumulation is due to the incompletely digested material from autophagic vacuoles. Furthermore, a deficiency in PrP C may disrupt the autophagic flux by inhibiting autophagosome-lysosomal fusion. Overall, our results provide insight into the protective role of PrP C in neurons, which may play a role in normal behavior and other brain functions.

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          Most cited references59

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          Guidelines for the use and interpretation of assays for monitoring autophagy.

          In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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            Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.

            PrPC is a host protein anchored to the outer surface of neurons and to a lesser extent of lymphocytes and other cells. The transmissible agent (prion) responsible for scrapie is believed to be a modified form of PrPC. Mice homozygous for disrupted PrP genes have been generated. Surprisingly, they develop and behave normally for at least seven months, and no immunological defects are apparent. It is now feasible to determine whether mice devoid of PrPC can propagate prions and are susceptible to scrapie pathogenesis.
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              Molecular biology of prion diseases.

              Prions cause transmissible and genetic neurodegenerative diseases, including scrapie and bovine spongiform encephalopathy of animals and Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases of humans. Infectious prion particles are composed largely, if not entirely, of an abnormal isoform of the prion protein, which is encoded by a chromosomal gene. A posttranslational process, as yet unidentified, converts the cellular prion protein into an abnormal isoform. Scrapie incubation times, neuropathology, and prion synthesis in transgenic mice are controlled by the prion protein gene. Point mutations in the prion protein genes of animals and humans are genetically linked to development of neuro-degeneration. Transgenic mice expressing mutant prion proteins spontaneously develop neurologic dysfunction and spongiform neuropathology. Understanding prion diseases may advance investigations of other neurodegenerative disorders and of the processes by which neurons differentiate, function for decades, and then grow senescent.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                08 July 2014
                25 August 2014
                2014
                : 6
                : 207
                Affiliations
                [1] 1Ilsong Institute of Life Science, Hallym University Anyang, Gyeonggi-do, South Korea
                [2] 2New York State Institute for Basic Research in Developmental Disabilities Staten Island, NY, USA
                [3] 3Department of Biomedical Gerontology, Graduate School of Hallym University Chuncheon, Gangwon-do, South Korea
                [4] 4Department of Microbiology, College of Medicine, Hallym University Chuncheon, Gangwon-do, South Korea
                Author notes

                Edited by: Xiongwei Zhu, Case Western Reserve University, USA

                Reviewed by: Hyoung-gon Lee, Case Western Reserve University, USA; Xinglong Wang, Case Western Reserve University, USA

                *Correspondence: Eun-Kyoung Choi and Yong-Sun Kim, Ilsong Institute of Life Science, Hallym University, 15 Gwanpyeong-ro 170 beon-gil, Anyang, Gyeonggi-do 1605-4, South Korea e-mail: ekchoi@ 123456hallym.ac.kr ; yskim@ 123456hallym.ac.kr

                This article was submitted to the journal Frontiers in Aging Neuroscience.

                Article
                10.3389/fnagi.2014.00207
                4142790
                25202268
                70a9bd0b-bac6-489f-b56b-9f43da065495
                Copyright © 2014 Shin, Park, Carp, Choi and Kim.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 June 2014
                : 25 July 2014
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 71, Pages: 12, Words: 7372
                Categories
                Neuroscience
                Original Research Article

                Neurosciences
                prion protein,autophagy,autophagic flux,lipofuscin pigmented autophagy,prnp-deficient mice

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