Molecular crowding accelerates fibrillization of alpha-synuclein: could an increase in the cytoplasmic protein concentration induce Parkinson's disease?

Biochemistry
Mark D ShtilermanP T Lansbury

Abstract

Parkinson's disease (PD) is one of many neurodegenerative diseases that are characterized by amyloid fibril formation. Alpha-synuclein is a primary component of the fibrillar neuronal inclusions, known as Lewy bodies, that are diagnostic of PD. In addition, the alpha-synuclein gene is linked to familial PD. Fibril formation by alpha-synuclein proceeds via discrete beta-sheet-rich oligomers, or protofibrils, that are consumed as fibrils grow. Both FPD mutations accelerate formation of protofibrils, suggesting that these intermediates, rather than the fibril product, trigger neuronal loss. In idiopathic PD, other factors may be responsible for accelerating protofibril formation by wild-type alpha-synuclein. One possible factor could be molecular crowding in the neuronal cytoplasm. We demonstrate here that crowding using inert polymers significantly reduced the lag time for protofibril formation and the conversion of the protofibril to the fibril, but did not affect the morphology of either species. Physiologically realistic changes in the degree of in vitro crowding have significant kinetic consequences. Thus, nonspecific changes in the total cytoplasmic protein concentration, induced by cell volume changes and/or altered protein...Continue Reading

References

May 1, 1967·American Journal of Clinical Pathology·S M Saeed, G Fine
Jan 1, 1983·Journal of Neurology·M Tomonaga
Jan 1, 1993·Annual Review of Biophysics and Biomolecular Structure·S B Zimmerman, A P Minton
Dec 1, 1995·Biophysical Chemistry·R Lindner, G Ralston
Sep 29, 1998·Methods in Enzymology·S H WhiteK Hristova
Dec 29, 1998·Journal of Bacteriology·M B ElowitzS Leibler
Feb 19, 2000·Current Opinion in Structural Biology·A P Minton
Apr 5, 2001·Journal of Molecular Biology·D EliezerG Browne
Aug 3, 2001·Nature Reviews. Neuroscience·K S McNaughtP Jenner
Jan 10, 1996·Accounts of Chemical Research·Judith Herzfeld

❮ Previous
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Citations

Feb 9, 2010·European Biophysics Journal : EBJ·Steven S-S WangBo-Wei Wang
Sep 28, 2010·Biomolecular NMR Assignments·Kuen-Phon Wu, Jean Baum
Jul 8, 2011·Neurotoxicity Research·Li Rebekah Feng, Kathleen A Maguire-Zeiss
May 12, 2004·Biochimica Et Biophysica Acta·Vladimir N Uversky, Anthony L Fink
Jun 20, 2003·Neuropharmacology·Kumlesh K DevHerman van der Putten
Jul 25, 2003·Biochimica Et Biophysica Acta·Damien Hall, Allen P Minton
Jul 31, 2008·Biochemistry·Larissa A MunishkinaVladimir N Uversky
Mar 26, 2010·Journal of the American Chemical Society·Duncan A WhiteChristopher M Dobson
Sep 5, 2008·Nature Reviews. Neuroscience·Patrik BrundinTamas Revesz
Sep 28, 2013·Molecular BioSystems·Leonid BreydoVladimir N Uversky
Dec 11, 2002·The European Journal of Neuroscience·Kevin St P McNaughtC Warren Olanow
Jul 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Kazuhiro AokiMichiyuki Matsuda
Apr 24, 2013·Proceedings of the National Academy of Sciences of the United States of America·Leonardus M I KoharudinAngela M Gronenborn
Sep 15, 2009·The Journal of Biological Chemistry·Zheng ZhouYi Liang
Sep 19, 2012·The Journal of Biological Chemistry·Chiu Fan LeeDavid J Vaux
Dec 23, 2008·The Journal of Biological Chemistry·Rakez KayedCharles Glabe
Feb 27, 2009·Antioxidants & Redox Signaling·Jeanne M M TanKah-Leong Lim
Jun 15, 2007·Nucleic Acids Research·Yoshiharu SasakiNaoki Sugimoto
Jul 22, 2004·European Journal of Biochemistry·Euijung JoJoAnne McLaurin
Feb 20, 2008·Biochemistry. Biokhimii︠a︡·N A Chebotareva
Jun 15, 2005·Annual Review of Biochemistry·Mark R Cookson
Jul 10, 2010·PLoS Computational Biology·Hao DongHuan-Xiang Zhou
Jun 3, 2006·Biological Chemistry·R John Ellis, Allen P Minton
Nov 29, 2013·International Journal of Molecular Sciences·Qian MaYi Liang
Oct 7, 2011·The Journal of Chemical Physics·Leili Javidpour, Muhammad Sahimi
May 14, 2003·Proceedings of the National Academy of Sciences of the United States of America·Ariel FernándezR Stephen Berry
Jan 6, 2010·EMBO Molecular Medicine·Tjakko J van HamEllen A A Nollen
Apr 21, 2005·Proceedings of the National Academy of Sciences of the United States of America·Gary J Pielak
Dec 28, 2012·Biochimica Et Biophysica Acta·Vladimir N Uversky
Jun 12, 2014·Journal of Biochemistry·Shruti Mittal, Laishram Rajendrakumar Singh
May 16, 2006·Nature Chemical Biology·David W ColbyK Dane Wittrup
Mar 2, 2005·Nature Reviews. Genetics·Jose L BadanoNicholas Katsanis
Dec 17, 2014·International Journal of Molecular Sciences·Irina M KuznetsovaVladimir N Uversky
Jun 15, 2007·Expert Review of Neurotherapeutics·Ennio EspositoGiuseppe Di Giovanni

❮ Previous
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