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Selective Transgenic Expression of Mutant Ubiquitin in Purkinje Cell Stripes in the Cerebellum

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      Abstract

      The ubiquitin-proteasome system (UPS) is one of the major mechanisms for protein breakdown in cells, targeting proteins for degradation by enzymatically conjugating them to ubiquitin molecules. Intracellular accumulation of ubiquitin-B +1 (UBB +1), a frameshift mutant of ubiquitin-B, is indicative of a dysfunctional UPS and has been implicated in several disorders, including neurodegenerative disease. UBB +1-expressing transgenic mice display widespread labeling for UBB +1 in brain and exhibit behavioral deficits. Here, we show that UBB +1 is specifically expressed in a subset of parasagittal stripes of Purkinje cells in the cerebellar cortex of a UBB +1-expressing mouse model. This expression pattern is reminiscent of that of the constitutively expressed Purkinje cell antigen HSP25, a small heat shock protein with neuroprotective properties.

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      Most cited references 26

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      Protein degradation and protection against misfolded or damaged proteins.

       Tony Goldberg (2003)
      The ultimate mechanism that cells use to ensure the quality of intracellular proteins is the selective destruction of misfolded or damaged polypeptides. In eukaryotic cells, the large ATP-dependent proteolytic machine, the 26S proteasome, prevents the accumulation of non-functional, potentially toxic proteins. This process is of particular importance in protecting cells against harsh conditions (for example, heat shock or oxidative stress) and in a variety of diseases (for example, cystic fibrosis and the major neurodegenerative diseases). A full understanding of the pathogenesis of the protein-folding diseases will require greater knowledge of how misfolded proteins are recognized and selectively degraded.
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        Proteolysis: from the lysosome to ubiquitin and the proteasome.

        How the genetic code is translated into proteins was a key focus of biological research before the 1980s, but how these proteins are degraded remained a neglected area. With the discovery of the lysosome, it was suggested that cellular proteins are degraded in this organelle. However, several independent lines of experimental evidence strongly indicated that non-lysosomal pathways have an important role in intracellular proteolysis, although their identity and mechanisms of action remained obscure. The discovery of the ubiquitin-proteasome system resolved this enigma.
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          The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg.

          The ubiquitin-proteasome system targets numerous cellular proteins for degradation. In addition, modifications by ubiquitin-like proteins as well as proteins containing ubiquitin-interacting and -associated motifs modulate many others. This tightly controlled process involves multiple specific and general enzymes of the system as well as many modifying and ancillary proteins. Thus, it is not surprising that ubiquitin-mediated degradation/processing/modification regulates a broad array of basic cellular processes. Moreover, aberrations in the system have been implicated, either as a primary cause or secondary consequence, in the pathogenesis of both inherited and acquired neurodegenerative diseases. Recent findings indicate that the system is involved in the pathogenesis of Parkinson's, Alzheimer's, Huntington's, and Prion diseases as well as amyotrophic lateral sclerosis. This raises hopes for a better understanding of the pathogenetic mechanisms involved in these diseases and for the development of novel, mechanism-based therapeutic modalities.
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            Author and article information

            Affiliations
            [1 ]ISNI 0000 0001 0481 6099, GRID grid.5012.6, Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, , Maastricht University, ; Maastricht, The Netherlands
            [2 ]ISNI 0000000090126352, GRID grid.7692.a, Lab of Experimental Neurology, Brain Center Rudolf Magnus, , University Medical Center Utrecht, ; Utrecht, The Netherlands
            [3 ]ISNI 0000 0004 1936 8200, GRID grid.55602.34, Department of Medical Neuroscience, , Dalhousie University, ; Halifax, Nova Scotia Canada
            Contributors
            l.m.verheijen-3@umcutrecht.nl
            Journal
            Cerebellum
            Cerebellum
            Cerebellum (London, England)
            Springer US (New York )
            1473-4222
            1473-4230
            13 December 2016
            13 December 2016
            2017
            : 16
            : 3
            : 746-750
            27966098 5427096 838 10.1007/s12311-016-0838-1
            © The Author(s) 2016

            Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

            Funding
            Funded by: Internationale Stiching Alzheimer Onderzoek
            Award ID: 06502 and 09514
            Funded by: Hersenstichting Nederland
            Award ID: 2008.17 and 15F07.48
            Categories
            Short Reports
            Custom metadata
            © Springer Science+Business Media New York 2017

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