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Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular ?-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 ?-synuclein deposition and may play a key role in the spreading of ?-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 ?-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 ?-synuclein, increased ?-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 ?-synuclein from the DMnX toward more rostral brain regions. In vitro experiments confirmed a greater propensity of ?-synuclein to pass from cell to cell under pro-oxidant conditions, and identified nitrated ?-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 ?-synuclein pathology and define a new mechanism, enhanced cell-to-cell ?-synuclein transmission, by which oxidative stress could promote PD development and progression.

SUBMITTER: Musgrove RE

PROVIDER: S-EPMC6715407 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Musgrove Ruth E RE Helwig Michael M Bae Eun-Jin EJ Aboutalebi Helia H Lee Seung-Jae SJ Ulusoy Ayse A Di Monte Donato A DA

The Journal of clinical investigation 20190613 9

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). Targe ...[more]

PMID: 31194700

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Project description:Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a central regulator of cellular stress responses and its transcriptional activation promotes multiple cellular defense and survival mechanisms. The loss of NRF2 has been shown to increase oxidative and proteotoxic stress, two key pathological features of neurodegenerative disorders such as Parkinson's disease (PD). Moreover, compromised redox homeostasis and protein quality control can cause the accumulation of pathogenic proteins, including alpha-synuclein (α-Syn) which plays a key role in PD. However, despite this link, the precise mechanisms by which NRF2 may regulate PD pathology is not clear. In this study, we generated a humanized mouse model to study the importance of NRF2 in the context of α-Syn-driven neuropathology in PD. Specifically, we developed NRF2 knockout and wild-type mice that overexpress human α-Syn (hα-Syn+/Nrf2-/- and hα-Syn+/Nrf2+/+ respectively) and tested changes in their behavior through nest building, challenging beam, and open field tests at three months of age. Cellular and molecular alterations in α-Syn, including phosphorylation and subsequent oligomerization, as well as changes in oxidative stress, inflammation, and autophagy were also assessed across multiple brain regions. It was observed that although monomeric α-Syn levels did not change, compared to their wild-type counterparts, hα-Syn+/Nrf2-/- mice exhibited increased phosphorylation and oligomerization of α-Syn. This was associated with a loss of tyrosine hydroxylase expressing dopaminergic neurons in the substantia nigra, and more pronounced behavioral deficits reminiscent of early-stage PD, in the hα-Syn+/Nrf2-/- mice. Furthermore, hα-Syn+/Nrf2-/- mice showed significantly amplified oxidative stress, greater expression of inflammatory markers, and signs of increased autophagic burden, especially in the midbrain, striatum and cortical brain regions. These results support an important role for NRF2, early in PD progression. More broadly, it indicates NRF2 biology as fundamental to PD pathogenesis and suggests that targeting NRF2 activation may delay the onset and progression of PD.

Dataset Information

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

Publications

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

Similar Datasets

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