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      The Mechanistic Links Between Proteasome Activity, Aging and Age-related Diseases

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          Abstract

          Damaged and misfolded proteins accumulate during the aging process, impairing cell function and tissue homeostasis. These perturbations to protein homeostasis (proteostasis) are hallmarks of age-related neurodegenerative disorders such as Alzheimer’s, Parkinson’s or Huntington’s disease. Damaged proteins are degraded by cellular clearance mechanisms such as the proteasome, a key component of the proteostasis network. Proteasome activity declines during aging, and proteasomal dysfunction is associated with late-onset disorders. Modulation of proteasome activity extends lifespan and protects organisms from symptoms associated with proteostasis disorders. Here we review the links between proteasome activity, aging and neurodegeneration. Additionally, strategies to modulate proteasome activity and delay the onset of diseases associated to proteasomal dysfunction are discussed herein.

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          Molecular chaperones in protein folding and proteostasis.

          Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.
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            Establishment in culture of pluripotential cells from mouse embryos.

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              Recognition and processing of ubiquitin-protein conjugates by the proteasome.

              The proteasome is an intricate molecular machine, which serves to degrade proteins following their conjugation to ubiquitin. Substrates dock onto the proteasome at its 19-subunit regulatory particle via a diverse set of ubiquitin receptors and are then translocated into an internal chamber within the 28-subunit proteolytic core particle (CP), where they are hydrolyzed. Substrate is threaded into the CP through a narrow gated channel, and thus translocation requires unfolding of the substrate. Six distinct ATPases in the regulatory particle appear to form a ring complex and to drive unfolding as well as translocation. ATP-dependent, degradation-coupled deubiquitination of the substrate is required both for efficient substrate degradation and for preventing the degradation of the ubiquitin tag. However, the proteasome also contains deubiquitinating enzymes (DUBs) that can remove ubiquitin before substrate degradation initiates, thus allowing some substrates to dissociate from the proteasome and escape degradation. Here we examine the key elements of this molecular machine and how they cooperate in the processing of proteolytic substrates.
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                Author and article information

                Journal
                Curr Genomics
                Curr. Genomics
                CG
                Current Genomics
                Bentham Science Publishers
                1389-2029
                1875-5488
                February 2014
                February 2014
                : 15
                : 1
                : 38-51
                Affiliations
                Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Co-logne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany
                Author notes
                [* ]Address correspondence to this author at the Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse, 26 50931 Cologne, Germany; Tel: +49 22147884172; E-mail: dvilchez@ 123456uni-koeln.de
                Article
                CG-15-38
                10.2174/138920291501140306113344
                3958958
                24653662
                501c8298-0a9a-44ae-8310-8f4ce31bd988
                ©2014 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                : 9 October 2013
                : 13 January 2014
                : 15 January 2014
                Categories
                Article

                Genetics
                aging,alzheimer’s disease,huntington’s disease,parkinson’s disease,proteasome,proteostasis,stem cells.

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