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Binding of alfa-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes
Linkoping Univ, Dept Clin Pathol, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
Linkoping Univ, Dept Clin Pathol, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
Univ Hosp Erlangen, Dept Mol Neurol, Erlangen, Germany.
Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
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2019 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 138, no 1, p. 23-47Article in journal (Refereed) Published
Abstract [en]

The intercellular transfer of alpha-synuclein (-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 -syn oligomeric assemblies (o-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and o-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked o-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with -syn accumulation. Notably, we could alsodemonstrate a direct interaction between -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 -synucleinopathies.

Place, publisher, year, edition, pages
SPRINGER , 2019. Vol. 138, no 1, p. 23-47
Keywords [en]
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 (-syn)
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Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-390089DOI: 10.1007/s00401-019-02007-xISI: 000471708700002PubMedID: 30976973OAI: oai:DiVA.org:uu-390089DiVA, id: diva2:1340412
Funder
Swedish Research Council, 523-2013-2735German Research Foundation (DFG), GRK2162Available from: 2019-08-05 Created: 2019-08-05 Last updated: 2019-08-05Bibliographically approved

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