Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes

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Abstract

The intercellular transfer of alpha-synuclein (α-syn) has been implicated in the progression of Parkinson’s disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of α-syn oligomeric assemblies (oα-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and oα-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked oα-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with α-syn accumulation. Notably, we could also demonstrate a direct interaction between α-syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related α-synucleinopathies.

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The online version of this article (10.1007/s00401-019-02007-x) contains supplementary material, which is available to authorized users.

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Most cited references 61

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alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies.

M Spillantini, R A Crowther, R. Jakes … (1998)

Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of alpha-synuclein, showing the presence of full-length or close to full-length alpha-synuclein. The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended alpha-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

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The SH-SY5Y cell line in Parkinson’s disease research: a systematic review

Helena Xicoy, Bé Wieringa, Gerard Martens (2017)

Parkinson’s disease (PD) is a devastating and highly prevalent neurodegenerative disease for which only symptomatic treatment is available. In order to develop a truly effective disease-modifying therapy, improvement of our current understanding of the molecular and cellular mechanisms underlying PD pathogenesis and progression is crucial. For this purpose, standardization of research protocols and disease models is necessary. As human dopaminergic neurons, the cells mainly affected in PD, are difficult to obtain and maintain as primary cells, current PD research is mostly performed with permanently established neuronal cell models, in particular the neuroblastoma SH-SY5Y lineage. This cell line is frequently chosen because of its human origin, catecholaminergic (though not strictly dopaminergic) neuronal properties, and ease of maintenance. However, there is no consensus on many fundamental aspects that are associated with its use, such as the effects of culture media composition and of variations in differentiation protocols. Here we present the outcome of a systematic review of scientific articles that have used SH-SY5Y cells to explore PD. We describe the cell source, culture conditions, differentiation protocols, methods/approaches used to mimic PD and the preclinical validation of the SH-SY5Y findings by employing alternative cellular and animal models. Thus, this overview may help to standardize the use of the SH-SY5Y cell line in PD research and serve as a future user’s guide. Electronic supplementary material The online version of this article (doi:10.1186/s13024-017-0149-0) contains supplementary material, which is available to authorized users.

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Transmission of multiple system atrophy prions to transgenic mice.

J Watts, K. Giles, A. Oehler … (2013)

Prions are proteins that adopt alternative conformations, which become self-propagating. Increasing evidence argues that prions feature in the synucleinopathies that include Parkinson's disease, Lewy body dementia, and multiple system atrophy (MSA). Although TgM83(+/+) mice homozygous for a mutant A53T α-synuclein transgene begin developing CNS dysfunction spontaneously at ∼10 mo of age, uninoculated TgM83(+/-) mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain α-synuclein prions, we inoculated the TgM83(+/-) mice with brain homogenates from two pathologically confirmed MSA cases. Inoculated TgM83(+/-) mice developed progressive signs of neurologic disease with an incubation period of ∼100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83(+/+) mice developed neurologic dysfunction in ∼210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated α-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions. The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago.

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Author and article information

Contributors

Juan F. Reyes: juan.reyes@liu.se

Martin Hallbeck: martin.hallbeck@liu.se

Journal

Journal ID (nlm-ta): Acta Neuropathol

Journal ID (iso-abbrev): Acta Neuropathol

Title: Acta Neuropathologica

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0001-6322

ISSN (Electronic): 1432-0533

Publication date (Electronic): 11 April 2019

Publication date PMC-release: 11 April 2019

Publication date (Print): 2019

Volume: 138

Issue: 1

Pages: 23-47

Affiliations

[1 ]ISNI 0000 0001 2162 9922, GRID grid.5640.7, Department of Clinical Pathology and Department of Clinical and Experimental Medicine, , Linköping University, ; Linköping, Sweden

[2 ]ISNI 0000 0000 9935 6525, GRID grid.411668.c, Department of Molecular Neurology, , University Hospital Erlangen, ; Erlangen, Germany

[3 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Clinical Neuroscience, , Karolinska Institute, ; Stockholm, Sweden

[4 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Section of Geriatrics, Department of Public Health and Caring Sciences, , Uppsala University, ; Uppsala, Sweden

Article

Publisher ID: 2007

DOI: 10.1007/s00401-019-02007-x

PMC ID: 6570706

PubMed ID: 30976973

SO-VID: b6e219e7-4701-4ab3-a0b9-714b938e93f4

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 28 September 2018

Date revision received : 3 April 2019

Date accepted : 3 April 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;

Award ID: 523-2013-2735

Award Recipient : Martin Hallbeck

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ScienceOpen disciplines: Neurology

Keywords: parkinson’s disease (pd),multiple system atrophy (msa),alzheimer’s disease (ad),cell-to-cell transfer,prion-like transfer,gap junction proteins,cx32,gjb1,alpha-synuclein (α-syn)

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ScienceOpen disciplines: Neurology

Keywords: parkinson’s disease (pd), multiple system atrophy (msa), alzheimer’s disease (ad), cell-to-cell transfer, prion-like transfer, gap junction proteins, cx32, gjb1, alpha-synuclein (α-syn)

Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes

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Karger: Neurology and Neuroscience

Most cited references 61

alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies.

The SH-SY5Y cell line in Parkinson’s disease research: a systematic review

Transmission of multiple system atrophy prions to transgenic mice.

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