Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins

  • William P. Flavin
  • Luc Bousset
  • Zachary C. Green
  • Yaping Chu
  • Stratos Skarpathiotis
  • Michael J. Chaney
  • Jeffrey H. Kordower
  • Ronald Melki
  • Edward M. Campbell
Original Article

DOI: 10.1007/s00401-017-1722-x

Cite this article as:
Flavin, W.P., Bousset, L., Green, Z.C. et al. Acta Neuropathol (2017). doi:10.1007/s00401-017-1722-x

Abstract

Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis. The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.

Keywords

α-Synuclein Tau Huntingtin Endocytic vesicle rupture Galectin 3 Lewy body 

Supplementary material

401_2017_1722_MOESM1_ESM.pdf (1.5 mb)
Supplementary material 1 (PDF 1558 kb)

Supplementary material 2 (MP4 824 kb)

Supplementary material 3 (MP4 861 kb)

Supplementary material 4 (MP4 829 kb)

Supplementary material 5 (MP4 659 kb)

Supplementary material 6 (MP4 451 kb)

401_2017_1722_MOESM7_ESM.docx (35 kb)
Supplementary material 7 (DOCX 35 kb)

Funding information

Funder NameGrant NumberFunding Note
Michael J. Fox Foundation for Parkinson's Research
    Parkinson's Disease Foundation
      Agence Nationale de la Recherche
      • ANR-14-CE13-0031
      EC Joint Programme on Neurodegenerative Diseases
      • JPND-NeuTARGETs-ANR-14-JPCD-0002-02; JPND-SYNACTION-ANR-15-JPWG-0012-03
      Centre National de la Recherche Scientifique
        Association France Parkinson
        • contract 113344
        Fondation de France
        • contract 2015-00060936
        Fondation Bettencourt-Schueller
          Fondation Simone et Cino Del Duca
            Achievement Rewards for College Scientists Foundation
              Arthur J. Schmitt Foundation
                The Fondation pour la Recherche Médicale
                • contract DEQ20160334896

                Copyright information

                © Springer-Verlag Berlin Heidelberg 2017

                Authors and Affiliations

                • William P. Flavin
                  • 1
                  • 2
                • Luc Bousset
                  • 3
                • Zachary C. Green
                  • 4
                • Yaping Chu
                  • 5
                • Stratos Skarpathiotis
                  • 1
                • Michael J. Chaney
                  • 6
                • Jeffrey H. Kordower
                  • 5
                  • 7
                • Ronald Melki
                  • 3
                • Edward M. Campbell
                  • 2
                  • 4
                  • 6
                  • 8
                1. 1.Stritch School of MedicineLoyola University ChicagoMaywoodUSA
                2. 2.Integrative Cell Biology ProgramLoyola University ChicagoMaywoodUSA
                3. 3.Paris-Saclay Institute of NeuroscienceCNRSGif-sur-YvetteFrance
                4. 4.Neuroscience ProgramLoyola University ChicagoMaywoodUSA
                5. 5.Department of Neurological SciencesRush University Medical CenterChicagoUSA
                6. 6.Department of Microbiology and ImmunologyLoyola University ChicagoMaywoodUSA
                7. 7.Center for Neurodegenerative ScienceVan Andel InstituteGrand RapidsUSA
                8. 8.Loyola University ChicagoMaywoodUSA

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