Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer.
J Clin Invest
; 129(9): 3738-3753, 2019 06 13.
Article
em En
| MEDLINE
| ID: mdl-31194700
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 reactive oxidative species (ROS). Targeted α-synuclein overexpression within these neurons triggered an oxidative stress that became significantly 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 pro-oxidant 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 new mechanism, enhanced cell-to-cell α-synuclein transmission, by which oxidative stress could promote PD development and progression.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
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Nervo Vago
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Estresse Oxidativo
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Alfa-Sinucleína
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Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article