Editors' ChoiceParkinson’s Disease

Mind the gap: Cx32 and α-synuclein

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Science Translational Medicine  15 May 2019:
Vol. 11, Issue 492, eaax4874
DOI: 10.1126/scitranslmed.aax4874

Abstract

α-synuclein oligomer uptake by neurons and oligodendrocytes exploits connexin-32.

Soluble oligomeric complexes of certain proteins and peptides have been proposed to exhibit causative roles in the pathogenesis of neurodegenerative diseases. The question of how oligomer assemblies transfer from cell to cell, resulting in prion-like spread during disease, is complicated and controversial. Identifying transfer pathways and pathway components has the potential to provide new therapeutic targets that can stop the spread of disease within the brain.

During Parkinson’s disease (PD) and multiple system atrophy (MSA), oligomers of α-synuclein (α-syn) are implicated in cell-to-cell propagation and neurotoxicity. Reyes et al. used an elegant, multifaceted approach to demonstrate that the gap junction protein connexin-32 (Cx32) facilitates preferential uptake of α-syn oligomeric complexes. The authors showed that genetic modulation of Cx32 protein expression or pharmacological modulation of activity alter α-syn uptake by neurons and oligodendrocytes. Uptake facilitated by Cx32 was greatest for oligomeric species, as opposed to monomeric or fibrillar forms. A direct correlation between α-syn protein concentration and Cx32 up-regulation further indicated a feedback cycle between these two proteins and was confirmed in transgenic mouse models of PD and MSA. Furthermore, coimmunoprecipitation of Cx32 with α-syn was observed in two out of four brain samples derived from PD patients but was not observed in control donor samples. Here, the story becomes more complicated with Cx32 down-regulated in the regions of human brain vulnerable to PD and MSA. To explain this result, the authors speculated of a protective down-regulation response to reduce α-syn uptake and accumulation as disease progresses.

Although it is unlikely to be the only means of transfer, the interaction between Cx32 and α-syn oligomer uptake revealed in this study may offer a potential target for disruption or slowing of pathogenesis. Supporting this assertion, the authors were able to demonstrate that inhibition of Cx32-containing gap junctions slowed the uptake of α-syn. The down-regulation of Cx32 within the affected human PD brain, however, raises questions—primarily how effective further inhibiting the Cx32–α-syn interaction would be and when intervention would have to commence. Nevertheless, the identified interaction provides an intricate insight into the spread of α-syn oligomers within the ailing brain.

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