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Cited by 186Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsNuclear Receptors and Signaling

The DOI matches its Crossref record; 246 of the 248 references it cites were found in a registry or an index.

Neuron-Astrocyte Interactions in Parkinson’s Disease

Open access
Miyazaki, Ikuko, Asanuma, Masato·2020·Cells
DOI 10.3390/cells9122623PMC PMC7762285
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Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

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Figure 1 Neuron-astrocyte interaction under neuropathological conditions. Neurotoxic A1 astrocytes, induced by activated microglia, upregulate proinflammatory factors, such as IL-1α, IL-1β and TNF-α and produce neuroinflammation. Microglia-released proinflammatory mediators, such as TNF-α, IL-1β, and IFN-γ, inhibit glutamate uptake in astrocytes leading to glutamate toxicity. Nrf2 system disruption in astrocytes leads to decrease in antioxidative molecules, which results in oxidative stress. Damaged neurons release aggregated α-synuclein and damaged mitochondria. Neuron-to-astrocyte transmission of α-synuclein, followed by its accumulation and deposition in astrocytes, produces proinflammatory cytokines and impairs glutamate uptake via GLT-1.
Figure 1 Neuron-astrocyte interaction under neuropathological conditions. Neurotoxic A1 astrocytes, induced by activated microglia, upregulate proinflammatory factors, such as IL-1α, IL-1β and TNF-α and produce neuroinflammation. Microglia-released proinflammatory mediators, such as TNF-α, IL-1β, and IFN-γ, inhibit glutamate uptake in astrocytes leading to glutamate toxicity. Nrf2 system disruption in astrocytes leads to decrease in antioxidative molecules, which results in oxidative stress. Damaged neurons release aggregated α-synuclein and damaged mitochondria. Neuron-to-astrocyte transmission of α-synuclein, followed by its accumulation and deposition in astrocytes, produces proinflammatory cytokines and impairs glutamate uptake via GLT-1.CC BY · PubMed Central
Figure 2 Targeting molecules in astrocytes for dopaminergic neuroprotection. Upregulation of astrocytic xCT increases GSH synthesis leading to neuroprotection against oxidative stress. GLT-1 plays an important role in inhibiting glutamate toxicity. GLT-1 and xCT cooperate for continuous cystine uptake followed by GSH synthesis. MTs bind Cu with a high affinity and inhibit Cu-induced α-synuclein aggregation. The stimulation of 5-HT1A receptor on astrocytes activates the Nrf2 signaling pathway followed by the upregulation of antioxidants including GSH-related molecules and MTs. Astrocytes engulf the aggregated α-synuclein and damaged mitochondria released from neuronal cells and degrade these neuronal waste via the proteasome and autophagy pathways.
Figure 2 Targeting molecules in astrocytes for dopaminergic neuroprotection. Upregulation of astrocytic xCT increases GSH synthesis leading to neuroprotection against oxidative stress. GLT-1 plays an important role in inhibiting glutamate toxicity. GLT-1 and xCT cooperate for continuous cystine uptake followed by GSH synthesis. MTs bind Cu with a high affinity and inhibit Cu-induced α-synuclein aggregation. The stimulation of 5-HT1A receptor on astrocytes activates the Nrf2 signaling pathway followed by the upregulation of antioxidants including GSH-related molecules and MTs. Astrocytes engulf the aggregated α-synuclein and damaged mitochondria released from neuronal cells and degrade these neuronal waste via the proteasome and autophagy pathways.CC BY · PubMed Central

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Metadata

Authors
Miyazaki, I., & Asanuma, M.
Affiliations
Okayama University (JP)
Corresponding author
Miyazaki, Ikuko
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2020-12-07
Volume
9
Issue
12
Pages
2623
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells9122623
PMC
PMC7762285
OpenAlex
W3111143057
Cited by
186
References
248
Citations by year
2026: 37 · 2025: 36 · 2024: 34 · 2023: 35 · 2022: 31 · 2021: 13
FWCI
2.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
  • Okayama University Scientific Achievement Repository (Okayama University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Japan Society for the Promotion of Science (JP25461279, JP16K09673, JP19K07993)
  • Okayama Medical Foundation (2014)
  • All Japan Coffee Association (2016, 2018)
  • Japanese Society of Eucommia (2018)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, astrocyte-neuron interaction, astrocytes, dopaminergic neurons, neurodegeneration, neuroinflammation, inflammatory cytokines, glial cells, disease-modifying therapy, neuroprotection
MeSH terms
Neuroprotection, Animals, Antioxidants, Astrocytes, Dopamine, Humans, Inflammation, Mitochondria, Nerve Degeneration, Neuroglia, Neurons, Parkinson Disease, Signal Transduction, Oxidative Stress, Disease Progression, alpha-Synuclein, Dopaminergic Neurons

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