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

Autor: Jürgen Winkler, Martin Hallbeck, Martin Ingelsson, Per Svenningsson, Christopher Sackmann, Alana Hoffmann, Juan F. Reyes
Rok vydání: 2019
Předmět:
0301 basic medicine
Gap Junction Proteins
Multiple system atrophy (MSA)
animal diseases
Alzheimer’s disease (AD)
Connexins
Cx32
Mice
0302 clinical medicine
Protein uptake
heterocyclic compounds
Prion-like transfer
Neurons
Chemistry
Brain
GJB1
Parkinson Disease
Parkinson’s disease (PD)
Cell biology
Oligodendroglia
Alzheimer's disease (AD)
alpha-Synuclein
Parkinsons disease (PD)
Alzheimers disease (AD)
Cell-to-cell transfer
Gap junction proteins
alpha-Synuclein (-syn)
Neurovetenskaper
Intracellular
Parkinson's disease (PD)
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
Atrophy
stomatognathic system
mental disorders
medicine
Animals
Original Paper
urogenital system
alpha-Synuclein (α-syn)
Neurosciences
Multiple System Atrophy
medicine.disease
nervous system diseases
030104 developmental biology
nervous system
α synuclein
Neurology (clinical)
030217 neurology & neurosurgery
Zdroj: Acta Neuropathologica
ISSN: 1432-0533
0001-6322
Popis: 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. Electronic supplementary material The online version of this article (10.1007/s00401-019-02007-x) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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