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Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer
Ruth E. Musgrove, … , Ayse Ulusoy, Donato A. Di Monte
Ruth E. Musgrove, … , Ayse Ulusoy, Donato A. Di Monte
Published June 13, 2019
Citation Information: J Clin Invest. 2019;129(9):3738-3753. https://doi.org/10.1172/JCI127330.
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Research Article Neuroscience

Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer

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Abstract

Specific neuronal populations display high vulnerability to pathological processes in Parkinson’s disease (PD). The dorsal motor nucleus of the vagus nerve (DMnX) is a primary site of pathological α-synuclein deposition and may play a key role in the spreading of α-synuclein lesions within and outside the CNS. Using in vivo models, we show that cholinergic neurons forming this nucleus are particularly susceptible to oxidative challenges and accumulation of ROS. Targeted α-synuclein overexpression within these neurons triggered an oxidative stress that became more pronounced after exposure to the ROS-generating agent paraquat. A more severe oxidative stress resulted in enhanced production of oxidatively modified forms of α-synuclein, increased α-synuclein aggregation into oligomeric species, and marked degeneration of DMnX neurons. Enhanced oxidative stress also affected neuron-to-neuron protein transfer, causing an increased spreading of α-synuclein from the DMnX toward more rostral brain regions. In vitro experiments confirmed a greater propensity of α-synuclein to pass from cell to cell under prooxidant conditions and identified nitrated α-synuclein forms as highly transferable protein species. These findings substantiate the relevance of oxidative injury in PD pathogenetic processes, establish a relationship between oxidative stress and vulnerability to α-synuclein pathology, and define a mechanism, enhanced cell-to-cell α-synuclein transmission, by which oxidative stress could promote PD development and progression.

Authors

Ruth E. Musgrove, Michael Helwig, Eun-Jin Bae, Helia Aboutalebi, Seung-Jae Lee, Ayse Ulusoy, Donato A. Di Monte

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Figure 8

Cell-to-cell hα-synuclein exchange is promoted by oxidative stress in vitro.

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Cell-to-cell hα-synuclein exchange is promoted by oxidative stress in vi...
(A) Cocultures of V1S- and SV2-expressing cells were incubated for 2 days with vehicle (n = 6 separate experiments, gray bar) or different concentrations of paraquat (n = 6/concentration, red bars). Cell viability was measured and expressed as percentage of vehicle-treated cultures. (B) Levels of hα-synuclein were measured in cocultures treated with vehicle (n = 6) or 25 μM paraquat (n = 6) by ELISA. (C and D) Representative images show accumulation of nitrated hα-synuclein in the form of hα-synuclein/3-NT PLA dots (red). Cell nuclei were stained with DAPI (blue). Scale bar: 10 μm. The number of PLA dots was counted in cultures treated with vehicle (n = 4) or paraquat (n = 4). A minimum of 100 cells/experiment were analyzed. PLA counts were divided by the number of cells, and values were averaged. (E) Representative images show BiFC (green) as a marker of hα-synuclein transfer into recipient cells. Scale bar: 20 μm. (F and G) The percentage of BiFC-positive cells (n = 6/treatment, F) and cell fluorescence intensity (n = 6/treatment, G) were compared in cultures treated with vehicle or paraquat. Integrated density of BiFC fluorescence was measured in a minimum of 400 cells/experiment and expressed as percentage of the mean value in vehicle-treated cultures. (H and I) Representative images show hα-synuclein/3-NT PLA (red) and BiFC (green) fluorescence. The arrow indicates lack of signal colocalization, while the arrowheads show colocalization. Scale bar: 5 μm. The percentage of BiFC aggregates colocalizing with PLA was calculated in cultures treated with vehicle (n = 4) or paraquat (n = 4). Minimum 100 cells/experiment. (J and K) Representative images show BiFC (green) in cocultures treated with saline or paraquat in the presence of IgG, anti–3-NT, or anti-nitrated α-synuclein (nSyn12). Scale bar: 20 μm. The percentage of BiFC-positive cells (n = 6/treatment) was calculated under different treatment conditions. *P ≤ 0.05; **P ≤ 0.01, Mann-Whitney U test or Kruskal-Wallis followed by Dunn’s post hoc test (K).
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