Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal
  • Top
  • Abstract
  • Selective susceptibility to stress
  • Effect of α-Syn on oxidative stress
  • Oxidative stress promotes α-Syn transfer
  • Conclusions and future directions
  • Footnotes
  • References
  • Version history
  • Article usage
  • Citations to this article

Advertisement

Commentary Free access | 10.1172/JCI130351

Oxidative stress and α-synuclein conspire in vulnerable neurons to promote Parkinson’s disease progression

Kelvin C. Luk

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Kelvin C. Luk, 1/F Maloney Building, 3600 Spruce Street, Philadelphia, Pennsylvania 19104, USA. Phone: 215.615.3202; Email: kelvincl@pennmedicine.upenn.edu.

Find articles by Luk, K. in: PubMed | Google Scholar |

Published August 5, 2019 - More info

Published in Volume 129, Issue 9 on September 3, 2019
J Clin Invest. 2019;129(9):3530–3531. https://doi.org/10.1172/JCI130351.
© 2019 American Society for Clinical Investigation
Published August 5, 2019 - Version history
View PDF

Related article:

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
Research Article Neuroscience

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

  • Text
  • PDF
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

×

Abstract

Patients with Parkinson’s disease (PD) show selective degeneration of dopaminergic neurons in the substantia nigra and cholinergic neurons in the dorsal motor nucleus (DMnX), but the drivers of this specific susceptibility are unknown. In this issue of the JCI, Musgrove et al. report on their use of an impressive array of in vivo and ex vivo tools for interrogating DMnX neurons and demonstrate that this population exhibits enhanced sensitivity to oxidative stress. Remarkably, this sensitivity was amplified by the overexpression of α-Synuclein (α-Syn), a pathological protein in PD. They further show that oxidative stress augments cell-cell transfer of α-Syn, which may be an important mechanism underlying the development and progression of PD.

Selective susceptibility to stress

Selective neuronal loss is a characteristic feature of neurodegenerative diseases. In patients with Parkinson’s disease (PD), for example, targeted degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) is well documented (1). Yet the relative sparing of dopamine-producing ventral tegmental area neurons in these individuals indicates that not all neurons with the same neurotransmitter are equally vulnerable (2). While the precise reasons for the selective vulnerability of the SNpc remain to be fully defined, intrinsic properties, such as high energy demand, extensive axonal arborization, and elevated cytosolic calcium levels, have emerged as factors that differentiate cells that succumb to or withstand neurodegenerative insults (3). The presence of α-synuclein (α-Syn), a central component of Lewy bodies and neurites in PD brains, also contributes to neuronal stress, as knockout or reduction of this protein ameliorates toxicity in several models of SNpc cell death (4–6).

Analogous to SNpc dopaminergic neurons, cholinergic neurons also show differential vulnerability in PD, with projection neurons of the dorsal motor nucleus (DMnX) representing one of the earliest populations to accumulate in α-Syn pathology in the CNS (1, 7). Like SNpc neurons, DMnX neurons stand out from other cholinergic populations in the hypoglossal nucleus, medial septum, and striatum, in which cell loss is limited.

In this issue, Musgrove et al. (8) report on their investigation of the sensitivity of cholinergic DMnX neurons to intraperitoneal injection of paraquat, a bipirydyl herbicide that catalyzes the formation of ROS and induces the degeneration of SNpc neurons in mice (9). They show that paraquat results in a significant increase in ROS in cholinergic DMnX neurons within days of treatment. Importantly, ROS levels monitored using the superoxide-sensitive indicator dihydroethidium (DHE) remained unchanged in cholinergic neurons in the neighboring hypoglossal nucleus, medial septal nucleus, and the striatum of wild-type mice, pointing to the selective sensitivity in the DMnX among cells expressing this neurotransmitter. However, in contrast to SNpc dopamine neurons, cholinergic neurons did not degenerate following paraquat treatment alone in the regions examined.

Effect of α-Syn on oxidative stress

Since vagal cholinergic neurons are one of the earliest populations to accumulate α-Syn containing Lewy bodies in PD (1), the authors examined whether overexpression of α-Syn could also modulate oxidative stress in these cells. Unilateral injection of adeno-associated virus (AAV) particles encoding human α-Syn (hα-Syn) into the vagus nerve increased basal ROS levels in DMnX neurons that expressed hα-Syn. While only 40% of DMnX neurons were immunoreactive for hα-Syn, oxidized DHE levels were approximately 30% higher in these cells than in neurons lacking hα-Syn. Treatment with paraquat further increased ROS levels by 1.5-fold and reduced the total number of surviving DMnX neurons by 25% after 7 days, suggesting a toxic synergy between oxidative stress and α-Syn in these cells.

To test whether these combined insults in DMnX neurons also generated higher levels of modified α-Syn typical of human synucleinopathies, Musgrove et al. probed DMnX neurons with antibodies raised against oxidized or nitrated hα-Syn. Consistent with the oxidative environment induced by paraquat and hα-Syn AAV, modified hα-Syn could be detected in both neuronal processes and cell bodies by immunostaining and ELISA. Curiously, the accumulated α-Syn species were also detectable with an antibody recognizing both oligomeric and fibrillar recombinant hα-Syn, but not with an α-Syn fibril-specific antibody (10). This differs somewhat from human PD pathology, where fibrillar α-Syn species predominate (6), although this observation may be a function of the short treatment durations used; whether these α-Syn species later mature into intraneuronal pathology resembling classical Lewy bodies and neurites after prolonged exposure to oxidative conditions remains to be seen.

Oxidative stress promotes α-Syn transfer

Although the cholinergic DMnX neurons do not project to more rostral CNS regions, they receive input from neurons in the pons and ventral midbrain (11). Previous work from the Di Monte group had shown that AAV-expressed hα-Syn can be transferred in a retrograde fashion from the vagus to more rostral regions, such as pons and midbrain (12). In the present study, Musgrove et al. show that treatment with paraquat more than doubled the density of hα-Syn immunoreactive processes in these rostral regions. Moreover, proximity ligation assay labeling with a 3-nitrotyrosine–specific antibody confirmed that the hα-Syn contained within these axons was nitrated, though it was unclear whether this modification occurred while in the donor (i.e., DMnX) neurons or after transfer to recipient axons. To further address this question, the authors turned to a cell-based model to measure the effect of oxidative stress on intercellular α-Syn transfer in cocultures of two SH-SY5Y cell lines expressing complementary fragments of the Venus fluorescent protein (13). Both paraquat and hydrogen peroxide dramatically increased the proportion of cells with bimolecular fluorescence without altering total α-Syn levels. Intriguingly, this transfer could be blocked with antibodies specifically recognizing nitrated α-Syn. Further studies are required to resolve whether nitrated α-Syn species are more readily released into the extracellular space or whether nitration facilitates α-Syn uptake by neurons. Nonetheless, this observation suggests that oxidative stress enhances the cell-to-cell transmission of α-Syn and is consistent with the in vivo finding of increased nitrated hα-Syn in CNS regions connected to the DMnX.

What is the source of ROS in DMnX neurons following paraquat exposure? Past studies have shown that NADPH oxidase is a potent catalyst for ROS formation from paraquat. Interestingly, mice lacking gp91phox, a subunit of the membrane-bound NADPH oxidase present in microglia, are protected against SNpc neuron loss after paraquat treatment (14). Here, Musgrove et al. demonstrated that the ROS accumulation induced by paraquat and hα-Syn overexpression was absent in the cholinergic DMnX neurons of gp91phox–/– mice, thus implicating surrounding microglia as the major source of ROS in these neurons. While this further supports the notion that the source of ROS in neurons originates from neighboring glial cells, it also raises the question of whether microglia surrounding DMnX and SNpc neurons differ functionally from other microglia or whether vulnerable neurons provide prooxidative signals to the local environment.

Conclusions and future directions

In summary, these provocative findings provide a fresh perspective on how a triad of processes frequently implicated in PD (i.e., oxidative stress, α-Syn, and microglia) converge at a subpopulation of neurons, leading to their selective degeneration. One possible scenario is that chronic exposure to environmental toxins such as paraquat primes DMnX cholinergic and other vulnerable neurons, causing them to later exhibit increased α-Syn pathology formation and dissemination. Alternatively, misfolded α-Syn is a potent trigger for microglia, and early accumulation of Lewy pathology in DMnX neurons could trigger a neuroinflammatory cascade, leading to oxidative stress that disproportionately affects these cells (15, 16). These processes are also not mutually exclusive. Establishing the sequence in which each of these events (co-)occur will therefore be a crucial next step to translating these findings into a better understanding of human disease.

Footnotes

Conflict of interest: The author has declared that no conflict of interest exists.

Copyright: © 2019, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2019;129(9):3530–3531. https://doi.org/10.1172/JCI130351.

See the related article at Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer.

References
  1. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197–211.
    View this article via: PubMed CrossRef Google Scholar
  2. Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain. 1991;114(Pt 5):2283–2301.
    View this article via: PubMed Google Scholar
  3. Sulzer D, Surmeier DJ. Neuronal vulnerability, pathogenesis, and Parkinson’s disease. Mov Disord. 2013;28(6):715–724.
    View this article via: PubMed CrossRef Google Scholar
  4. Dauer W, et al. Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci U S A. 2002;99(22):14524–14529.
    View this article via: PubMed CrossRef Google Scholar
  5. Mosharov EV, et al. Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron. 2009;62(2):218–229.
    View this article via: PubMed CrossRef Google Scholar
  6. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci U S A. 1998;95(11):6469–6473.
    View this article via: PubMed CrossRef Google Scholar
  7. Halliday GM, et al. Neuropathology of immunohistochemically identified brainstem neurons in Parkinson’s disease. Ann Neurol. 1990;27(4):373–385.
    View this article via: PubMed CrossRef Google Scholar
  8. Musgrove RE, et al. Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular-synuclein transfer. J Clin Invest. 2019;129(9):3738–3753.
    View this article via: JCI PubMed Google Scholar
  9. McCormack AL, et al. Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis. 2002;10(2):119–127.
    View this article via: PubMed CrossRef Google Scholar
  10. Vaikath NN, et al. Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology. Neurobiol Dis. 2015;79:81–99.
    View this article via: PubMed CrossRef Google Scholar
  11. Kalia M, Sullivan JM. Brainstem projections of sensory and motor components of the vagus nerve in the rat. J Comp Neurol. 1982;211(3):248–265.
    View this article via: PubMed CrossRef Google Scholar
  12. Ulusoy A, et al. Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol Med. 2013;5(7):1119–1127.
    View this article via: PubMed CrossRef Google Scholar
  13. Bae EJ, et al. Glucocerebrosidase depletion enhances cell-to-cell transmission of α-synuclein. Nat Commun. 2014;5:4755.
    View this article via: PubMed Google Scholar
  14. Purisai MG, McCormack AL, Cumine S, Li J, Isla MZ, Di Monte DA. Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. Neurobiol Dis. 2007;25(2):392–400.
    View this article via: PubMed CrossRef Google Scholar
  15. Kim C, et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun. 2013;4:1562.
    View this article via: PubMed Google Scholar
  16. Yun SP, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med. 2018;24(7):931–938.
    View this article via: PubMed CrossRef Google Scholar
Version history
  • Version 1 (August 5, 2019): Electronic publication
  • Version 2 (September 3, 2019): Print issue publication

Article tools

  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal

Metrics

  • Article usage
  • Citations to this article

Go to

  • Top
  • Abstract
  • Selective susceptibility to stress
  • Effect of α-Syn on oxidative stress
  • Oxidative stress promotes α-Syn transfer
  • Conclusions and future directions
  • Footnotes
  • References
  • Version history
Advertisement
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts