Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson's disease

Proceedings of the National Academy of Sciences of the United States of America
Mohamed-Bilal FaresH A Lashuel

Abstract

Lewy bodies (LBs) are intraneuronal inclusions consisting primarily of fibrillized human α-synuclein (hα-Syn) protein, which represent the major pathological hallmark of Parkinson's disease (PD). Although doubling hα-Syn expression provokes LB pathology in humans, hα-Syn overexpression does not trigger the formation of fibrillar LB-like inclusions in mice. We hypothesized that interactions between exogenous hα-Syn and endogenous mouse synuclein homologs could be attenuating hα-Syn fibrillization in mice, and therefore, we systematically assessed hα-Syn aggregation propensity in neurons derived from α-Syn-KO, β-Syn-KO, γ-Syn-KO, and triple-KO mice lacking expression of all three synuclein homologs. Herein, we show that hα-Syn forms hyperphosphorylated (at S129) and ubiquitin-positive LB-like inclusions in primary neurons of α-Syn-KO, β-Syn-KO, and triple-KO mice, as well as in transgenic α-Syn-KO mouse brains in vivo. Importantly, correlative light and electron microscopy, immunogold labeling, and thioflavin-S binding established their fibrillar ultrastructure, and fluorescence recovery after photobleaching/photoconversion experiments showed that these inclusions grow in size and incorporate soluble proteins. We further investig...Continue Reading

References

May 26, 1995·Science·W A Eaton, J Hofrichter
Aug 28, 1997·Nature·M G SpillantiniM Goedert
May 30, 1998·Proceedings of the National Academy of Sciences of the United States of America·M G SpillantiniM Goedert
Apr 4, 2000·Nature·M B Feany, W W Bender
Nov 7, 2000·Human Molecular Genetics·S J TabriziA H Schapira
Sep 29, 2001·Science·P HammarströmJ W Kelly
Oct 10, 2001·BMC Neuroscience·C G Specht, R Schoepfer
Nov 29, 2001·The Journal of Biological Chemistry·He-Jin LeeSeung-Jae Lee
Jan 29, 2002·Nature Cell Biology·Hideo FujiwaraTakeshi Iwatsubo
Oct 16, 2002·The Journal of Biological Chemistry·Masato HasegawaTakeshi Iwatsubo
Nov 5, 2002·The American Journal of Pathology·Mónica Mendes SousaMaria João Saraiva
Nov 25, 2003·The Journal of Biological Chemistry·Mikiei TanakaM Maral Mouradian
Oct 7, 2004·Proceedings of the National Academy of Sciences of the United States of America·Sreeganga ChandraThomas C Südhof
Dec 9, 2004·Neurobiology of Aging·Deborah E CabinRobert L Nussbaum
Nov 22, 2005·Neurobiology of Disease·Peter KlivenyiM Flint Beal
Apr 14, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·George K TofarisMaria Grazia Spillantini
Apr 16, 2008·Journal of Neurochemistry·Felipe OpazoBjörn H Falkenburger
Oct 30, 2008·Journal of Neuropathology and Experimental Neurology·Li-Wen KoShu-Hui C Yen
Jan 27, 2009·Nature Methods·Sean A McKinneyLoren L Looger
Feb 6, 2009·Molecular Neurodegeneration·Mark R Cookson
Mar 6, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Katerina E PaleologouHilal A Lashuel
Jun 16, 2010·Neuron·Ted M DawsonValina L Dawson
Jul 7, 2010·Journal of Molecular Biology·Hiofan HoiRobert E Campbell
May 20, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sabina AnwarVladimir L Buchman
Feb 4, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Abid OueslatiHilal A Lashuel
Dec 21, 2012·Nature Reviews. Neuroscience·Hilal A LashuelEliezer Masliah

❮ Previous
Next ❯

Citations

Sep 8, 2016·Frontiers in Synaptic Neuroscience·Isabell Begemann, Milos Galic
Feb 9, 2017·Nature Medicine·Yvette C Wong, Dimitri Krainc
Nov 29, 2016·The European Journal of Neuroscience·Natalie LandeckDeniz Kirik
Dec 1, 2017·NPJ Parkinson's Disease·Bryan Andrew Killinger, Viviane Labrie
Feb 9, 2018·Movement Disorders : Official Journal of the Movement Disorder Society·Rose B Creed, Matthew S Goldberg
Jun 6, 2018·Cell and Tissue Research·Suzanne Chartier, Charles Duyckaerts
Mar 31, 2019·Disease Models & Mechanisms·Teresa R Taylor-WhiteleyDavid P Smith
Apr 21, 2019·Journal of Neurochemistry·Amir Tayaranian MarvianTiago Fleming Outeiro
May 3, 2018·Journal of Neuropathology and Experimental Neurology·Owen Scudamore, Thomas Ciossek
Dec 4, 2019·Nature Neuroscience·Angus LauJoel C Watts
Jan 9, 2020·FEBS Letters·Zachary A SorrentinoBenoit I Giasson
May 20, 2020·The Journal of Biological Chemistry·Zachary A Sorrentino, Benoit I Giasson
May 10, 2016·Movement Disorders : Official Journal of the Movement Disorder Society·Natalia Lopez-Gonzalez Del Rey
Mar 12, 2017·Journal of Parkinson's Disease·Michel GoedertMaria Grazia Spillantini
Oct 4, 2019·Brain : a Journal of Neurology·Yaping ChuJeffrey H Kordower
Jan 18, 2019·Proceedings of the National Academy of Sciences of the United States of America·Paul M LevineMatthew R Pratt
Feb 23, 2020·Proceedings of the National Academy of Sciences of the United States of America·Anne-Laure Mahul-MellierHilal A Lashuel
Sep 10, 2020·Molecular Neurodegeneration·Natalie LandeckJean-Christophe Rochet
May 12, 2020·Frontiers in Pharmacology·Mónica Gómez-BenitoRosario Moratalla
Jan 13, 2021·Nature Reviews. Neuroscience·Mohamed Bilal FaresHilal A Lashuel
Apr 22, 2021·Brain : a Journal of Neurology·Nathalie Van Den BergePer Borghammer
May 5, 2021·The Journal of Physical Chemistry Letters·Tianyi DouDmitry Kurouski
Jul 15, 2021·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Alexander SvanbergssonJia-Yi Li

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alpha-Synuclein Aggregation

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.

Alpha-Synuclein Aggregation (MDS)

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.