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

Reyes JF, Sackmann C, Hoffmann A, Svenningsson P, Winkler J, Ingelsson M, Hallbeck M (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Acta Neuropathologica Springer

Book Volume: 138

Pages Range: 23-47

Journal Issue: 1

DOI: 10.1007/s00401-019-02007-x

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.

Authors with CRIS profile

Alana Hoffmann Professur für Molekulare Neurologie Jürgen Winkler Professur für Molekulare Neurologie

Involved external institutions

Linköping University SE Sweden (SE) Karolinska Institute SE Sweden (SE) Uppsala University SE Sweden (SE)

How to cite

APA:

Reyes, J.F., Sackmann, C., Hoffmann, A., Svenningsson, P., Winkler, J., Ingelsson, M., & Hallbeck, M. (2019). Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes. Acta Neuropathologica, 138(1), 23-47. https://dx.doi.org/10.1007/s00401-019-02007-x

MLA:

Reyes, Juan F., et al. "Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes." Acta Neuropathologica 138.1 (2019): 23-47.

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