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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 6

Oxidatively modified hα-synuclein is accumulated within pontine axons during caudo-rostral spreading of the protein.

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Oxidatively modified hα-synuclein is accumulated within pontine axons du...
Mice received an infusion of hα-synuclein–carrying AAVs into the left vagus nerve and were injected systemically with either saline or paraquat and sacrificed at 7 days after treatment. (A) Nitrated hα-synuclein was detected by indirect hα-synuclein/3-NT PLA. The number of PLA dots in the left pons from mice treated with hα-synuclein AAVs/saline (n = 4, gray bar) or with hα-synuclein AAVs/paraquat (n = 5, red bar) was counted. (B) Pontine tissue sections were costained with anti–3-NT and anti–hα-synuclein. Representative confocal images show labeled axons in the left pons. Scale bars: 5 μm. (C) Representative confocal images show axons in the left pons stained with anti-Syn 505 and anti–hα-synuclein. Scale bar: 5 μm. (D) Measurements of Syn 505 fluorescence were carried out in the left pons of mice treated with hα-synuclein AAVs/saline (n = 7) or with hα-synuclein AAVs/paraquat (n = 6). At least 3 axons/animal were analyzed and averaged. Values are expressed as percentage of the mean value in hα-synuclein AAV/saline-injected animals. Box and whisker plots show median, upper and lower quartiles, and maximum and minimum as whiskers. *P ≤ 0.05, Mann-Whitney U test.
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