Mihert Zenebe

Background: Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder globally. It is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra and aggregates of misfolded α-synuclein (α-syn) within the brain.^1,2 Individuals with PD may experience motor and non-motor symptoms that include shuffling gait and cognitive dysfunction.^1,3 While current PD therapies are effective regarding symptom management, none prevent the underlying neurodegeneration that causes disease progression. Thus, as DA neurons continue to decrease over time, therapies may become less adequate in improving quality of life.^2,4

Recently, astrocytes have been implicated in the pathogenesis of PD due to the presence of neurotoxic astrocytes in the postmortem brain tissue of individuals with PD.⁵ Astrocytes are essential to neuronal health, performing critical physiological functions such as the secretion of neurotrophic factors and mediating synaptic transmission. However, in pathological contexts, astrocytes can convert to a neurotoxic reactive state.^4,5 Preventing the formation of reactive astrocytes may be effective in future neuroprotective PD treatments.

Objective: In this review, we explore the role of reactive astrocytes in dopaminergic neuron degeneration, as well as the neuroprotective effects of reactive astrocyte downregulation in animal models of PD.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2025 using the following search terms: “Parkinson disease”, “astrocyte reactivity AND microglia AND Parkinson disease”.

Results: Astrocyte cultures derived from induced pluripotent stem cells obtained from PD patients secreted significantly higher levels of interleukin-6 (IL-6) when compared to the control. Inhibition of neuronal IL-6 receptors (IL-6R) significantly reduced caspase-3 mRNA expression in DA neurons treated with PD astrocyte-conditioned medium, indicating that astrocytes induce dopaminergic neuron death through IL-6/IL-6R signaling.⁵ In another experiment, α-syn synthesized by PD astrocytes was tracked using immunohistochemical staining of the FLAG peptide. FLAG-tagged α-syn was found to accumulate in DA neurons when co-cultured. This suggests that astrocytes contribute to neurodegeneration by distributing α-syn to surrounding neurons.⁶

Recent findings point to upstream microglial activation as a mechanism of reactive astrocyte induction. Intrastriatal injection of exosomes from microglia pre-treated with misfolded α-syn increased the number of C3d+ (a marker of astrocyte reactivity) astrocytes in the striatum in mice. PCR analysis of the exosomes revealed upregulation of pro-inflammatory molecules iNOS, TNFα, and IL6. Inhibition of microglial activation significantly reduced C3d+ astrocyte quantity when mice were treated with exosomes derived from misfolded α-syn-activated microglia.⁷ In a similar study, researchers inhibited microglial activation in a PD mouse model using NLY01, a glucagon-like peptide receptor 1 (GLP-1) agonist. These mice had greater levels of TH+ neurons in the substantia nigra pars compacta when compared to the control, and lower levels of pathological in α-syn aggregates in TH+ neurons.⁸

Conclusions: Recent discoveries in the literature suggest that PD pathogenesis involves microglial activation, which in turn causes the release of neurotoxic cytokines and pathological α-syn by reactive astrocytes.^5-7 Modulation of this neurodegenerative program is a potential mechanism of future neuroprotective PD therapies.^7,8 Future studies should investigate the safety of therapies such as GLP-1 agonists in human patients with PD.

Works Cited:

1. Khan MS, Nasiripour S, Bopassa JC. Parkinson Disease Signaling Pathways, Molecular Mechanisms, and Potential Therapeutic Strategies: A Comprehensive Review. Int J Mol Sci. 2025;26(13):6416. Published 2025 Jul 3. doi:10.3390/ijms26136416
2. Sonninen TM, Hämäläinen RH, Koskuvi M, et al. Metabolic alterations in Parkinson’s disease astrocytes. Sci Rep. 2020;10(1):14474. Published 2020 Sep 2. doi:10.1038/s41598-020-71329-8
3. Rawls A, Okun MS. Parkinson Disease. Continuum (Minneap Minn). 2025;31(4):930-955. doi:10.1212/cont.0000000000001593
4. Kam TI, Hinkle JT, Dawson TM, Dawson VL. Microglia and astrocyte dysfunction in parkinson’s disease. Neurobiol Dis. 2020;144:105028. doi:10.1016/j.nbd.2020.105028
5. Pons-Espinal M, Blasco-Agell L, Fernandez-Carasa I, et al. Blocking IL-6 signaling prevents astrocyte-induced neurodegeneration in an iPSC-based model of Parkinson’s disease. JCI Insight. 2024;9(3):e163359. Published 2024 Feb 8. doi:10.1172/jci.insight.163359
6. di Domenico A, Carola G, Calatayud C, et al. Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson’s Disease. Stem Cell Reports. 2019;12(2):213-229. doi:10.1016/j.stemcr.2018.12.011
7. Guo M, Guan A, Zhang M, et al. Exosome-mediated microglia-astrocyte interactions drive neuroinflammation in Parkinson’s disease with Peli1 as a potential therapeutic target. Pharmacol Res. 2025;219:107908. doi:10.1016/j.phrs.2025.107908
8. Yun SP, Kam TI, Panicker N, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med. 2018;24(7):931-938. doi:10.1038/s41591-018-0051-5