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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 September 3, 2019; First published June 13, 2019
Citation Information: J Clin Invest. 2019;129(9):3738-3753. https://doi.org/10.1172/JCI127330.
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Categories: 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 1

Paraquat-induced oxidative stress causes ROS accumulation in the DMnX, but not the hypoglossal nucleus.

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Paraquat-induced oxidative stress causes ROS accumulation in the DMnX, b...
(A) Mice received 2 i.p. injections of either saline or paraquat separated by a 1-week interval and were sacrificed at 2 days after treatment. They were also injected with DHE 1 hour before the time of sacrifice. Representative confocal images show fluorescent puncta of ox-DHE (a marker of ROS formation, blue-green-yellow color graded) within ChAT-immunoreactive neurons (magenta) in the DMnX. Scale bar: 5 μm. (B) Comparison of the integrated density of fluorescent ox-DHE puncta within ChAT-positive DMnX neurons from mice treated with saline (n = 4, light blue bar) or paraquat (n = 5, dark blue bar). Approximately 100 neurons/animal were analyzed and averaged. Values were calculated as percentage of the mean value in saline-injected animals. (C) Mice injected with saline (n = 4/time point) or paraquat (n = 4/time point) were sacrificed at 2 and 7 days after treatment, and the number of Nissl-stained neurons was counted unilaterally in the DMnX. (D) Representative confocal images show ChAT-positive hypoglossal neurons (magenta) containing fluorescent ox-DHE from mice injected with saline or paraquat and sacrificed 2 days after treatment. Scale bar: 5 μm. (E) Integrated density of ox-DHE puncta within ChAT-positive neurons in the hypoglossal nucleus. Analyses were carried out on tissue sections from mice treated with saline (n = 4) or paraquat (n = 5). Approximately 30 neurons/animal were analyzed and averaged. Values were calculated as percentage of the mean value in saline-injected animals. Box and whisker plots show median (middle line), upper and lower quartiles, and maximum and minimum as whiskers. *P ≤ 0.05, Mann-Whitney U test.
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