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      The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease

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          Abstract

          The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system ( UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease ( AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age‐related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS‐related therapies for AD.

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          A review on Alzheimer's disease pathophysiology and its management: an update.

          Anil Kumar Pinnaka, Arti Singh (2015)
          Alzheimer's disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Pathologically it is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. Over the last two decades, advances in the field of pathogenesis have inspired the researchers for the investigation of novel pharmacological therapeutics centered more towards the pathophysiological events of the disease. Currently available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N-methyl d-aspartate receptor antagonist (memantine) contribute minimal impact on the disease and target late aspects of the disease. These drugs decelerate the progression of the disease, provide symptomatic relief but fail to achieve a definite cure. While the neuropathological features of Alzheimer's disease are recognized but the intricacies of the mechanism have not been clearly defined. This lack of understanding regarding the pathogenic process may be the likely reason for the non-availability of effective treatment which can prevent onset and progression of the disease. Owing to the important progress in the field of pathophysiology in the last couple of years, new therapeutic targets are available that should render the underlying disease process to be tackled directly. In this review, authors will discusses the different aspects of pathophysiological mechanisms behind Alzheimer's disease and its management through conventional drug therapy, including modern investigational therapeutic strategies, recently completed and ongoing.
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            Structure and functions of the 20S and 26S proteasomes.

            O Coux, K Tanaka, A Goldberg (1996)
            The proteasome is an essential component of the ATP-dependent proteolytic pathway in eukaryotic cells and is responsible for the degradation of most cellular proteins. The 20S (700-kDa) proteasome contains multiple peptidase activities that function through a new type of proteolytic mechanism involving a threonine active site. The 26S (2000-kDa) complex, which degrades ubiquitinated proteins, contains in addition to the 20S proteasome a 19S regulatory complex composed of multiple ATPases and components necessary for binding protein substrates. The proteasome has been highly conserved during eukaryotic evolution, and simpler forms are even found in archaebacteria and eubacteria. Major advances have been achieved recently in our knowledge about the molecular organization of the 20S and 19S particles, their subunits, the proteasome's role in MHC-class 1 antigen presentation, and regulators of its activities. This article focuses on recent progress concerning the biochemical mechanisms and intracellular functions of the 20S and 26S proteasomes.
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              The 26S proteasome: a molecular machine designed for controlled proteolysis.

              D Voges, P Zwickl, W Baumeister (1999)
              In eukaryotic cells, most proteins in the cytosol and nucleus are degraded via the ubiquitin-proteasome pathway. The 26S proteasome is a 2.5-MDa molecular machine built from approximately 31 different subunits, which catalyzes protein degradation. It contains a barrel-shaped proteolytic core complex (the 20S proteasome), capped at one or both ends by 19S regulatory complexes, which recognize ubiquitinated proteins. The regulatory complexes are also implicated in unfolding and translocation of ubiquitinated targets into the interior of the 20S complex, where they are degraded to oligopeptides. Structure, assembly and enzymatic mechanism of the 20S complex have been elucidated, but the functional organization of the 19S complex is less well understood. Most subunits of the 19S complex have been identified, however, specific functions have been assigned to only a few. A low-resolution structure of the 26S proteasome has been obtained by electron microscopy, but the precise arrangement of subunits in the 19S complex is unclear.
              Article 0 comments Cited 271 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cell Mol Med
                Journal ID (iso-abbrev): J. Cell. Mol. Med
                Journal ID (doi): 10.1111/(ISSN)1582-4934
                Journal ID (publisher-id): JCMM
                Title: Journal of Cellular and Molecular Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1582-1838
                ISSN (Electronic): 1582-4934
                Publication date (Electronic): 29 March 2016
                Publication date (Print): July 2016
                Volume: 20
                Issue: 7 ( doiID: 10.1111/jcmm.2016.20.issue-7 )
                Pages: 1392-1407
                Affiliations
                [ 1 ] Laboratory of Neurobiology Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research (NIPER)Gauhati Medical College Guwahati AssamIndia
                [ 2 ] Institutional Level Biotech hub (IBT hub) Department of Biotechnology National Institute of Pharmaceutical Education and Research (NIPER)Gauhati Medical College Guwahati AssamIndia
                [ 3 ] Faculty of MedicineUniversity of Medicine and Pharmacy “Iuliu Hatieganu” Cluj‐NapocaRomania
                [ 4 ] Department of Clinical NeurosciencesUniversity of Medicine and Pharmacy “Iuliu Hatieganu” Cluj‐NapocaRomania
                [ 5 ]“RoNeuro” Institute for Neurological Research and Diagnostic Cluj‐NapocaRomania
                Author notes
                [*] [* ] Correspondence to: Dafin F. MURESANU

                E‐mail: dafinm@ 123456ssnn.ro

                [†]

                Kundlik Gadhave & Nityanand Bolshette contributed equally.

                Article
                Publisher ID: JCMM12817
                DOI: 10.1111/jcmm.12817
                PMC ID: 4929298
                PubMed ID: 27028664
                SO-VID: 63218b88-fc88-4550-8991-d55faccef495
                Copyright © © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
                License:

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 14 September 2015
                Date accepted : 17 January 2016
                Page count
                Pages: 16
                Categories
                Subject: Review Article
                Subject: Review Article
                Custom metadata
                source-schema-version-number 2.0
                component-id jcmm12817
                cover-date July 2016
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:01.07.2016

                ScienceOpen disciplines: Molecular medicine
                Keywords: ubiquitin,alzheimer's disease,amyloid β,chaperones
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: ubiquitin, alzheimer's disease, amyloid β, chaperones

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