Could a Common Mechanism of Protein Degradation Impairment Underlie Many Neurodegenerative Diseases?

Journal of Experimental Neuroscience
David M Smith

Abstract

At the cellular level, many neurodegenerative diseases (NDs), often considered proteinopathies, are characterized by the accumulation of misfolded and damaged proteins into large insoluble aggregates. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are amyloid β (Aβ) and tau in Alzheimer disease, α-synuclein (α-syn) in Parkinson disease, and polyQ-expanded huntingtin (Htt) in Huntington disease. Although significant efforts have focused on how the cell deals with these protein aggregates, why is it that these misfolded proteins are not degraded normally in the first place? A vast body of literature supports the notion that the cell's protein degradation system for individual proteins-the ubiquitin proteasome system (UPS)-does not function sufficiently in many NDs. The proteasome itself has received significant focus for years due to its obvious failure to degrade misfolded proteins in ND, but no general mechanism has been uncovered. We have recently found that specific pathologically relevant oligomers can potently and directly inhibit the proteasome. What is most interesting is that the misfolded protein's primary amino acid sequence was irrelevant to its ability to inhibit. Instead, ...Continue Reading

References

Jan 24, 1998·Brain Research·M M Tompkins, W D Hill
Jun 29, 2000·Annual Review of Biochemistry·D VogesW Baumeister
Aug 16, 2000·Proceedings of the National Academy of Sciences of the United States of America·Y A LamR Layfield
Oct 12, 2004·Molecular Neurobiology·Sophie VigourouxYves Briand
Mar 23, 2006·Nature Reviews. Neuroscience·Mark P Mattson, Tim Magnus
Jan 26, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Pascale N LacorWilliam L Klein
Jun 7, 2007·Nature Reviews. Neuroscience·Frank M LaFerlaSalvatore Oddo
Aug 10, 2007·Nature·Eric J BennettRon R Kopito
Oct 20, 2007·Human Molecular Genetics·Toshiaki TakahashiOsamu Onodera
May 13, 2008·Molecular Cell·Julius RablYifan Cheng
Aug 15, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Lynn BedfordR John Mayer
Jun 6, 2009·Annual Review of Biochemistry·Daniel Finley
Jun 9, 2009·Nature Cell Biology·Florence ClavagueraMarkus Tolnay
Aug 5, 2009·Proceedings of the National Academy of Sciences of the United States of America·Paula DesplatsSeung-Jae Lee
Aug 3, 2010·Biochimica Et Biophysica Acta·Nurit Livnat-Levanon, Michael H Glickman
Oct 5, 2010·Advances in Experimental Medicine and Biology·Niki Chondrogianni, Efstathios S Gonos
Jan 19, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Cristian A Lasagna-ReevesRakez Kayed
Mar 1, 2012·The Journal of Cell Biology·Mark S HippRon R Kopito
Mar 9, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Emanuela CollaMichael K Lee
Jun 8, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jonathan BrouilletteLuc Buée
Jul 24, 2012·Biochemical Society Transactions·Sarah M WardLester I Binder
Apr 30, 2013·Neurobiology of Learning and Memory·Timothy J Jarome, Fred J Helmstetter
Mar 22, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Diana L Castillo-CarranzaRakez Kayed
Mar 26, 2014·Brain : a Journal of Neurology·Edward RockensteinEliezer Masliah
Dec 24, 2014·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·UNKNOWN International Genomics of Alzheimer's Disease Consortium (IGAP)
Jan 7, 2015·Molecular Neurobiology·Yanuar Alan Sulistio, Klaus Heese
Sep 22, 2015·Frontiers in Molecular Neuroscience·Romina J Gentier, Fred W van Leeuwen
Mar 22, 2016·Biochemical and Biophysical Research Communications·Gilad LehmannAaron Ciechanover
Dec 13, 2016·Cold Spring Harbor Perspectives in Medicine·Maria Jimenez-SanchezDavid C Rubinsztein
Apr 28, 2017·Open Biology·Piotr BragoszewskiAgnieszka Chacinska

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Citations

Aug 2, 2019·Biological & Pharmaceutical Bulletin·Mutsumi OshimaHiroshi Katsuki
Apr 20, 2019·Frontiers in Molecular Biosciences·Talya ShachamGerardo Z Lederkremer
Sep 4, 2019·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·Carolina VaccariJoão Lauro de Camargo
Sep 11, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Alexandré Delport, Raymond Hewer
May 27, 2021·Journal of Agricultural and Food Chemistry·Hanieh NargehHamidreza Pazoki-Toroudi
Jul 3, 2021·International Journal of Molecular Sciences·Arnaud MarquetteBurkhard Bechinger
Aug 13, 2021·Brain : a Journal of Neurology·Jordan J S VerPlankAlfred L Goldberg

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