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.
View: Text | PDF
Research Article Neuroscience

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

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

×

Figure 7

Gp91phox-deficient mice are resistant to paraquat-induced DMnX pathology.

Options: View larger image (or click on image) Download as PowerPoint
Gp91phox-deficient mice are resistant to paraquat-induced DMnX pathology...
WT and gp91phox-deficient (KO) mice received an injection of hα-synuclein AAVs into the left vagus nerve and were injected systemically with either saline (n ≥ 4/genotype, gray bars) or paraquat (n ≥ 4/genotype, red bars) and sacrificed at 7 days. (A) Medullary tissue sections were processed for indirect hα-synuclein/3-NT PLA. Representative images show the left DMnX of a WT and a KO mouse injected with hα-synuclein AAVs/paraquat. Specific PLA signal was apparently reduced in the KO mouse. Scale bar: 10 μm. (B) The number of hα-synuclein/3-NT PLA dots was counted in the left DMnX of WT and KO mice injected with hα-synuclein AAVs/saline or hα-synuclein AAVs/paraquat. Values are expressed as percentage of the mean value in the corresponding hα-synuclein AAV/saline–injected animals. (C) Representative images of Nissl-stained neurons in the dorsal medulla oblongata. Tissues were obtained from a WT and a KO mouse injected with hα-synuclein AAVs/paraquat. The left DMnX is delineated in red. Neuronal loss is evident only in the left (ipsilateral to AAV infusion) DMnX from the WT animal. Scale bar: 100 μm. (D) The number of Nissl-stained neurons was counted stereologically in the left DMnX of WT and KO mice treated with hα-synuclein AAVs/saline or hα-synuclein AAVs/paraquat. Control counts (n = 5, light blue bar) were obtained from the right DMnX of WT animals injected with hα-synuclein AAVs/saline. (E and F) Pontine tissue sections were immunostained with anti–hα-synuclein. The schematic plots show the distribution of hα-synuclein–labeled axons in the left pons. In the graph, data show the counts of hα-synuclein–positive axons in the left pons. Box and whisker plots show median, upper and lower quartiles, and maximum and minimum as whiskers. **P ≤ 0.01; ***P ≤ 0.001, Mann-Whitney U test (saline- versus paraquat-injected mice) or Kruskal-Wallis followed by Dunn’s post hoc (D).