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Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Gothenburg, Sweden.
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2016 (English)In: PLOS ONE, ISSN 1932-6203, Vol. 11, no 12, article id e0168700Article in journal (Refereed) Published
Abstract [en]

Parkinsons disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha-synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE , 2016. Vol. 11, no 12, article id e0168700
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-134306DOI: 10.1371/journal.pone.0168700ISI: 000391222000063PubMedID: 28030591OAI: oai:DiVA.org:liu-134306DiVA, id: diva2:1071698
Note

Funding Agencies|Swedish Research Council [MH: 523-2013-2735]; Swedish Brain Power Program; Research Foundation of the Swedish Parkinsons Disease Association; Ostergotland Research Foundation for Parkinsons Disease; Parkinson Research Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Gustav V and Queen Victorias Foundation; Swedish Dementia Foundation; Linkoping University Neurobiology Centre; County Council of Ostergotland; Marianne and Marcus Wallenberg Foundation

Available from: 2017-02-06 Created: 2017-02-03 Last updated: 2018-01-13
In thesis
1. Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems
Open this publication in new window or tab >>Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are defined by neurodegeneration and accumulations of misfolded proteins that spread through the brain in a well characterized manner. In AD these accumulations consist mainly of β-amyloid (Aβ) and tau, while in PD, α-synuclein (α-syn) make up the characteristic lewy pathology. 

   The general aim of this thesis was to investigate mechanisms associated with neurotoxic peptide activity by Aβ, tau and α-syn in relation to cellular degradation and transfer with a cell-to-cell transfer model system.

   We found that intercellular transfer of oligomeric Aβ occurs independently of isoform. However, the amount of transfer correlates with each isoforms ability to resist degradation or cellular clearance. The Aβ1-42 isoform showed particular resistance to clearance, which resulted in higher levels of cell-to-cell transfer of the isoform and lysosomal stress caused by accumulation.

   As Aβ accumulations can inhibit the proteasomal degradation we investigated how reduced proteasomal degradation affected neuron-like cells. We found increased levels of phosphorylated tau protein, disturbed microtubule stability and impaired neuritic transport after reduced proteasomal activity. These changes was partly linked to c-Jun and ERK 1/2 kinase activity.

   We could also show that α-syn transferred from cell-to-cell in our model system, with a higher degree of transfer for the larger oligomer and fibrillar species. Similar to Aβ, α-syn mainly colocalized with lysosomes, before and after transfer.

    Lastly, we have developed our cell-to-cell transfer system into a model suitable for high throughput screening (HTS). The type of cells have been upgraded from SH-SY5Y cells to induced pluripotent stem cells (iPSCs), with a differentiation profile more similar to mature neurons. The next step will be screening a small molecular library for substances with inhibitory effect on cell-to-cell transfer of Aβ peptides. 

   The importance of the degradative systems in maintaining protein homeostasis and prevent toxic accumulations in general is well known. Our findings shows the importance of these systems for neurodegenerative diseases and also highlight the link between degradation and cell-to-cell transfer. To restore or enhance the degradative systems would be an interesting avenue to treat neurodegenerative diseases. Another way would be to inhibit the transfer of misfolded protein aggregates. By using the HTS model we developed, a candidate substance with good inhibitory effect on transfer can hopefully be found.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. p. 63
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1535
Keywords
Cell-to-cell transfer, beta-amyloid, Alzheimer's disease, degradation, proteasome, alpha-synuclein, Parkinson's disease, high throughput screening model
National Category
Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:liu:diva-134667 (URN)10.3384/diss.diva-134667 (DOI)9789176857014 (ISBN)
Public defence
2017-03-23, Linden, Campus US, Linköping, 13:00 (English)
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Available from: 2017-02-27 Created: 2017-02-23 Last updated: 2018-01-13Bibliographically approved

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Domert, JakobSackmann, ChristopherSeverinsson, EmelieAgholme, LottaHallbeck, Martin
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