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Cited by 1,045Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention

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Tansey, Malú G., Goldberg, Matthew S.·2010·Neurobiology of Disease
DOI 10.1016/j.nbd.2009.11.004PMC PMC2823829
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Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, after Alzheimer's disease. The potential causes of PD remain uncertain, but recent studies suggest neuroinflammation and microglia activation play important roles in PD pathogenesis. Major unanswered questions include whether protein aggregates cause the selective loss of dopaminergic neurons in the substantia nigra that underlies the clinical symptoms and whether neuroinflammation is a consequence or a cause of nigral cell loss. Within the microenvironment of the brain, glial cells play a critical role in homeostatic mechanisms that promote neuronal survival. Microglia have a specialized immune surveillance role and mediate innate immune responses to invading pathogens by secreting a myriad of factors that include, cytokines, chemokines, prostaglandins, reactive oxygen and nitrogen species, and growth factors. Some of these factors have neuroprotective and trophic activities and aid in brain repair processes; while others enhance oxidative stress and trigger apoptotic cascades in neurons. Therefore, pro- and anti-inflammatory responses must be in balance to prevent the potential detrimental effects of prolonged or unregulated inflammation-induced oxidative stress on vulnerable neuronal populations. In this review, we discuss potential triggers of neuroinflammation and review the strongest direct evidence that chronic neuroinflammation may have a more important role to play in PD versus other neurodegenerative diseases. Alternatively, we propose that genetic deficiency is not the only way to reduce protective factors in the brain which may function to keep microglial responses in check or regulate the sensitivity of DA neurons. If chronic inflammation can be shown to decrease the levels of neuroprotective factors in the midbrain, in essence genetic haploinsufficiency of protective factors such as Parkin or RGS10 may result from purely environmental triggers (aging, chronic systemic disease, etc.), increasing the vulnerability to inflammation-induced nigral DA neuron death and predisposing an individual to development of PD. Lastly, we review the latest epidemiological and experimental evidence supporting the potential use of anti-inflammatory and immunomodulatory drugs as neuroprotective agents to delay the progressive nigrostriatal degeneration that leads to motor dysfunction in PD.

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Crossref · 10.1016/j.nbd.2009.11.004

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  • Microglia are abundant in the substantia nigra of Parkinson's disease patients and, when activated by local neurodegeneration, produce O2•−, •NO, ONOO-, and pro-inflammatory cytokines that kill more neurons.

    “Microglia, the resident innate immune cells of the brain, are abundant in the substantia nigra of PD patients and when activated by local neurodegeneration they generate bursts of O2•−, •NO, ONOO–, and pro-inflammatory cytokines that kill additional neurons (209–213).”

    From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [212]

    The section ‘Evidence that neuroinflammation compromises dopaminergic neuron survival’ (page unavailable) describes activated microglia producing cytokines and reactive oxygen and nitrogen species, and says dying neurons may recruit more microglia whose respiratory bursts could increase oxidative stress. It also describes the midbrain as microglia-rich. But it does not establish that the listed species are all released by microglia in PD patients or that this process definitively kills additional neurons; it presents that outcome as a possible contribution to cell death. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Neuromelanin released by degenerating neurons is a potent microglial activator that induces neuroinflammation and neurodegeneration.

    “A potent activator of microglia is neuromelanin released by degenerating neurons, inducing neuroinflammation and neurodegeneration (114, 212).”

    From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [212]

    The section “Evidence that neuroinflammation compromises dopaminergic neuron survival” describes a cycle in which activated microglia promote inflammation and may contribute to neuronal death. It also says dying neurons may release chemoattractants that draw activated microglia. But the copy does not identify neuromelanin as the released substance or establish it as a potent microglial activator (searched: neuromelanin). (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Dying neurons release autolysosomal organelles containing neuromelanin, and these extracellular granules become sites where activated microglia proliferate.

    “Dying neurons release autolysosomal organelles containing neuromelanin and these extracellular granules become the sites where activated microglia proliferate (114, 212).”

    From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [212]

    In “Evidence that neuroinflammation compromises dopaminergic neuron survival” (page unavailable), the review says dying dopaminergic neurons may release chemoattractants that draw activated microglia to remove neuronal debris. It does not identify the released material as neuromelanin-containing autolysosomal organelles or say that microglia proliferate at extracellular granules. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Inflammation is a significant contributor to Parkinson's disease neuropathology.

    “While the etiology of PD is multifactorial, the role of inflammation has been deemed a significant contributor to neuropathology [3–5].”

    From Intrastriatal injection of preformed alpha-synuclein fibrils alters central and peripheral immune cell profiles in non-transgenic mice (2019) · cites this paper as [3]

  • Elevated levels of cytokines and prostaglandins have been detected in the cerebrospinal fluid and brains of PD patients, where they may activate microglia, induce migration of microglia to SN, and release pro-inflammatory cytokines and neurotoxic molecules capable of exacerbating the disease.

    “Elevated levels of cytokines and prostaglandins have been detected in the cerebrospinal fluid and brains of PD patients where they may in turn activate the microglia, induce migration of microglia to SN, and release pro-inflammatory cytokines, as well as neurotoxic molecules capable of further exacerbating the disease [453,454,455,456].”

    From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [455]

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Authors
Tansey, M. G., & Goldberg, M. S.
Affiliations
  • Emory University (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Tansey, Malú G.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2010-03
Volume
37
Issue
3
Pages
510-518
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2009.11.004
PMC
PMC2823829
OpenAlex
W1975774284
Cited by
1,045
References
142
Citations by year
2026: 41 · 2025: 37 · 2024: 55 · 2023: 66 · 2022: 59 · 2021: 83 · 2020: 102 · 2019: 78 · 2018: 76 · 2017: 67 · 2016: 61 · 2015: 72 · 2014: 51 · 2013: 57 · 2012: 63
FWCI
3.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Neurological Disorders and Stroke (R01NS049433)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, neuroinflammation, microglial activation, dopaminergic neuron death, substantia nigra, oxidative stress, neuroprotection, protein aggregates, Parkin, RGS10, haploinsufficiency, anti-inflammatory agents, immunomodulatory therapy, neurodegeneration
MeSH terms
Encephalitis, Environment, Immunologic Factors, Nerve Degeneration, Parkinson Disease, Microglia, Oxidative Stress, Cytoprotection, Ubiquitin-Protein Ligases

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