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

摘要

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 alpha-synuclein deposition and may play a key role in the spreading of alpha-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 alpha-synuclein overexpression within these neurons triggered an oxidative stress that became more pronounced after exposure to the ROSgenerating agent paraquat. A more severe oxidative stress resulted in enhanced production of oxidatively modified forms of alpha-synuclein, increased alpha-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 alpha-synuclein from the DMnX toward more rostral brain regions. In vitro experiments confirmed a greater propensity of alpha-synuclein to pass from cell to cell under prooxidant conditions and identified nitrated alpha-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 alpha-synuclein pathology, and define a mechanism, enhanced cell-to-cell alpha-synuclein transmission, by which oxidative stress could promote PD development and progression.