Astrocytes in Parkinson’s Disease: From Guardians to Accomplices

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of nigral dopaminergic neurons and misfolded α‑synuclein (α‑Syn) aggregation. However, increasing evidence indicates that astrocytes occupy a central position in the multifactorial pathogenesis of PD. As the most abundant glial cells in the Central Nervous System (CNS), astrocytes maintain neural homeostasis via neurotransmitter clearance, ion balance, metabolic support, synaptic regulation, and blood–brain barrier (BBB) integrity. In early PD, astrocytes exert neuroprotective effects; with disease progression, persistent pathological stimuli—including aggregated α-Syn, chronic neuroinflammation, mitochondrial dysfunction, oxidative stress, and iron dyshomeostasis—drive astrocytes into a reactive, neurotoxic state. This review systematically summarizes how astrocytes regulate α-Syn handling, mitochondrial function, neuroinflammation, and oxidative stress in PD, explaining how these pathways reshape astrocyte states across disease stages, and highlights stage-dependent dual roles of astrocytes as guardians and accomplices, with implications for astrocyte-targeted therapies.

Introduction

Parkinson’s disease (PD) is a common age-related progressive neurodegenerative disorder, first described in 1817, with a global prevalence exceeding 10 million.¹ It affects 1.5–2.0% of adults over 60 years and 4% of those over 80 years, with rising incidence and mortality in China.^2,3 PD manifests with motor symptoms (bradykinesia, tremor, muscle rigidity, gait disturbance, imbalance) and non-motor symptoms (cognitive impairment, mood disorders, sleep disturbances). Pathologically, PD is defined by loss of nigral dopaminergic neurons, α-Syn-positive Lewy pathology, and mitochondrial dysfunction.^4–7 Over 200 years since its first description, no disease‑modifying therapy exists; current treatments alleviate symptoms but do not halt progression.⁵ While neuronal loss is well‑studied, astrocyte contributions to PD pathogenesis have emerged as a critical focus. Astrocytes are the most abundant glial cells in the Central Nervous System (CNS) (20–50% of total cells), with star‑shaped morphology and extensive processes enwrapping neurons and blood vessels.^8–10 Under the microscope, they maintain neural homeostasis via ion balance, neurotransmitter clearance, metabolic support, synaptic regulation, and BBB integrity.^11–15 Astrocytes are implicated in multiple neurological disorders, including multiple sclerosis, Alzheimer’s disease, PD, Huntington’s disease, and neuropsychiatric conditions, such as depression, anxiety, and cognitive impairment.^16–18 In PD, senescent and reactive astrocytes create a pro-inflammatory milieu, exacerbating neuronal vulnerability.^19,20 Impaired astrocytic functions (BBB maintenance, glutamate homeostasis, metabolic support) further compromise neuronal survival.²¹ Thus, astrocytes are not passive bystanders but active regulators of PD progression.²² This review integrates recent advances on astrocyte-mediated mechanisms in PD, focusing on α-Syn handling, mitochondrial dysfunction, defined as impaired mitochondrial function and structure within astrocytes, neuroinflammation, and oxidative stress. Unlike most existing reviews that separately discuss single pathological cascade of astrocyte injury (α-Syn aggregation, mitochondrial damage or neuroinflammation alone), the present review constructs an integrated four-pathway interactive framework centered on stage-switching astrocytic function, systematically dissects the mutual crosstalk among α-Syn propagation, mitochondrial impairment, neuroinflammation and redox imbalance, further compares inconsistent findings from published literatures on astrocyte subtype heterogeneity and conflicting preclinical drug outcomes, and puts forward prospective therapeutic directions based on integrated pathological network.

The Dual Role of Astrocytes in Pathological α-Syn Spreading: From Clearance to Accomplice

α-Syn is a small presynaptic protein abundant in CNS neurons.²³ It consists of 140 amino acid with three key domains: an acetylated N-terminus (residues 1–60), an acidic C-terminus (residues 96–140), and a central non-amyloid-β component (NAC) domain (residues 61–95), which drives β-sheet formation and misfolding/aggregation/toxicity.^24,25 Physiologically, α-Syn balances α-helical monomers and tetramers.²⁶ Under pathological conditions, monomers assemble into toxic oligomers, an early driver of PD pathogenesis.^24,27 While α‑Syn aggregation is closely linked to PD, its exact mechanisms remain unclear.²³ Emerging evidence suggests the kidney may be an origin site of pathological α-Syn.²⁸ Under physiological conditions, α-Syn binds synaptic vesicle-associated membrane protein 2 (VAMP2) to regulate SNARE complex function, synaptic transmission, and integrity.^29,30 In PD, VAMP2 and α-Syn levels decline; loss of this interaction promotes abnormal α-Syn aggregation into Lewy bodies and Lewy neurites.²⁶ Aggregation is driven by intrinsic misfolding, cellular damage, SNCA mutations, and post-translational modifications (PTMs), including ubiquitination, SUMOylation, nitration, phosphorylation, and C-terminal truncation.^31–35 For example, SIAH-1-mediated ubiquitination promotes oligomerization, and phosphorylation of serine 129 is a key pathological hallmark.³⁶ These modifications synergize to accelerate aggregation and neurodegeneration, triggering widespread reactive astrogliosis that shifts astrocytes from “supporters” to “pathology facilitators”.^37–39 Astrocytes clear α‑Syn via the ubiquitin–proteasome system (UPS) and the autophagy–lysosomal pathway (ALP).^40,41 UPS uses Parkin/SIAH/Nedd4‑mediated ubiquitination for proteasomal degradation.^42,43 ALP involves chaperone-mediated, macro-, and microautophagy, with TFEB enhancing lysosomal clearance.⁴⁴ Excessive α‑Syn overloads these systems, causing astrocyte dysfunction and damage, turning them into a “double‑edged sword” in PD.^45,46 Notably, this phenomenon is not observed in the normal physiological state.^47,48 Under pathological conditions, astrocytes facilitate α-Syn transfer with neurons via endocytosis, tunneling nanotubes (TNTs), and extracellular vesicles (EVs), driving prion-like propagation.^49,50 Highly pathogenic Mini-P-type α-Syn exhibits even stronger transmissibility.⁵¹ The process of α‑Syn propagation is closely intertwined with its toxicity, as aggregated forms of the protein also act as a critical driver of the astrocytic shift from “friend” to “foe”. Pathological α-Syn induces reactive gliosis, increases glial fibrillary acidic protein (GFAP) expression, and triggers pro-inflammatory mediators release, including interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), IL-6, CCL2, and CXCL chemokines that drive neuroinflammatory responses.^52,53 Beyond inflammation, astrocytes are central regulators of excitotoxicity. Glutamate, the principal CNS excitatory neurotransmitter, is cleared from the synaptic cleft by astrocytic transporters, protecting neurons from excitotoxic injury.^54,55 Misfolded α-Syn drives pathology in part by downregulating key glutamate transporters, EAAT1/GLAST and EAAT2/GLT-1. Impaired glutamate uptake leads to extracellular accumulation, triggering Ca²⁺-mediated excitotoxicity and neuronal damage.^56,57 Pathological α-Syn oligomers also activate NF-κB signaling, promoting inflammatory mediators and reactive oxygen species (ROS). ROS impair glutamate transporters through two mechanisms: direct oxidation inhibits their function, while transcriptional downregulation reduces their expression. Together, this suppresses glutamate uptake, disrupts homeostasis, and exacerbates excitotoxic damage.^52,58 Meanwhile, α-Syn disrupts mitochondrial respiratory chain coupling and oxidative phosphorylation, elevating astrocytic ROS and oxidative stress.⁴⁸ Notably, α-Syn pathology directly induces astrocyte senescence, and interventions inhibiting aggregation or clearing senescent astrocytes improve degenerative state in midbrain organoid models.^59,60

Taken together, α-Syn pathology and astrocytic responses form a vicious cycle: protein aggregation, inflammatory amplification, excitotoxicity, and oxidative stress mutually reinforce one another, progressively converting astrocytes from supporters into amplifiers of PD progression. Of note, inconsistent experimental findings remain concerning the critical α‑Syn threshold triggering astrocytic functional switch, which awaits further in vivo verification to reconcile conflicting in vitro and animal-based outcomes (Figure 1).

Figure 1.

Schematic model of α-Syn pathological aggregation, transcellular propagation, and the bidirectional regulatory roles of astrocytes. This figure depicts the pathological cascade in PD, spanning from α-Syn misfolding and intercellular transmission to comprehensive astrocyte functional responses. Post-translational modifications including Ser129 phosphorylation, Lys6/10/12 ubiquitination and Tyr39 nitration drive pathological α-Syn aggregation, which shuttles bidirectionally between neurons and astrocytes via endocytosis, tunneling nanotubes (TNTs) and extracellular vesicles (EVs). At early PD stages, astrocytes exert neuroprotective effects by clearing aggregated α-Syn through the ubiquitin–proteasome system (UPS) and autophagy–lysosomal pathway (ALP). Once α-Syn accumulates excessively inside astrocytes, these cells switch to a harmful functional status, accompanied by elevated oxidative stress, robust secretion of proinflammatory mediators and defective glutamate clearance, which triggers neuronal excitotoxicity. Additionally, pathological α-Syn directly initiates astrocytic senescence and accelerates PD progression.

Abbreviations: α-Syn, α-Synuclein; Glu, glutamate; UPS, ubiquitin–proteasome system; ALP, autophagy–lysosomal pathway; TNTs, tunneling nanotubes; EVs, extracellular vesicles.

Astrocytic Mitochondrial Dysfunction in Parkinson’s Disease

Beyond α‑Syn‑mediated inflammation and excitotoxicity, mitochondrial dysfunction in astrocytes emerges as a central, early driver of PD pathogenesis. Mitochondrial dysfunction is increasingly recognized as a core pathological feature of PD, with astrocytic mitochondrial impairment playing a critical role. Mitochondria are central hubs for cellular metabolism, primarily generating adenosine triphosphate(ATP) via oxidative phosphorylation (OXPHOS). Their double-membrane structure supports the electron transport chain (ETC), enabling precise coordination of oxidative reactions.⁶¹ Beyond energy production, mitochondria play a key roles in maintaining calcium homeostasis, modulating apoptotic pathways, and preserving the cellular redox balance.⁶²

Astrocytes rely primarily on glycolysis for energy but still consume ~20% of brain oxygen, with mitochondrial OXPHOS governing synaptic homeostasis as well as the homeostasis of glutamate and calcium.^63,64 Thus, intact astrocytic mitochondria are essential for physiological function. Mitochondrial impairment disrupts energy metabolism, promotes excitotoxicity, dysregulates calcium signaling, and elevates oxidative stress, collectively driving dopaminergic neurodegeneration. Increasing body of evidence indicates that mitochondrial dysfunction in astrocytes is closely associated with the onset and progression of PD.^61,65–69 In astrocytes, key PD-related genes such as PINK1, PRKN, DJ-1, and LRRK2 regulate mitochondrial function, antioxidant response, and inflammatory signaling; their mutations impair mitophagy, accumulate damaged mitochondria, and activate chronic inflammatory pathways (NLRP3, cGAS‑STING), converting astrocytes into neurotoxic amplifiers.^70,71 PD patient-derived iPSC-astrocytes recapitulate mitochondrial dysfunction: reprogrammed metabolism, reduced OXPHOS, disrupted Ca²⁺ homeostasis, and exaggerated cytokine release upon inflammatory.^72,73 These alterations drive non-cell-autonomous neurodegeneration, positioning astrocytic mitochondrial dysfunction as a key pathological nexus integrating energy deficits, oxidative stress, excitotoxicity, and calcium dysregulation.⁷⁴ Mitochondria are the primary intracellular source of reactive oxygen species (ROS).⁷⁵ At physiological levels, mitochondrial ROS (mtROS) act as redox signaling molecules, activating antioxidant pathways such as the Nrf2-ARE system.^76,77 This triggers a defensive transcriptional program that upregulates detoxification genes—including those involved in glutathione metabolism, NQO1, and HO-1. This program bolsters the astrocytic capacity to preserve redox balance and stabilize the cerebral tissue microenvironment.^78,79 When ETC function is impaired or antioxidant defenses are insufficient, the production of superoxide anions and hydrogen peroxide increases, driving sustained oxidative stress and ultimately causing cell damage or death.^67,80 Astrocytes rely on key protective proteins to counteract mitochondrial ROS toxicity, with DJ-1 (PARK7) playing a pivotal role. DJ‑1, localized to astrocyte cytoplasm and around mitochondria, scavenging ROS, maintaining mitochondrial function, and inhibiting cell death. It regulates antioxidant genes via the Keap1-Nrf2 axis and modulates Bcl-xL, PI3K/PKB, and other pathways to mitigate oxidative stress and inflammatory responses.^57,81–83 In models of PD, loss of DJ-1 function or its oxidative modification compromises these protective mechanisms. This renders astrocytes more vulnerable to mitochondrial ROS (mtROS), thereby exacerbating the loss of dopaminergic neurons and accelerating disease progression.^81,82,84,85

Astrocytes are equipped with high concentrations of excitatory amino acid transporters (EAAT1/EAAT2) to mediate the uptake of synaptic glutamate into astrocytes, thereby facilitating its metabolic processing.⁸⁶ Through this regulatory mechanism, astrocytes sustain homeostatic glutamate levels, protecting neurons from excitotoxicity and death.⁸⁷ Glutamate is metabolized within the mitochondrial matrix via α-ketoglutarate dehydrogenase complex (KGDHC) and glutamate dehydrogenase (GDH), facilitate its entry into the tricarboxylic acid (TCA) cycle, thereby linking its detoxification to cellular energy production.^88,89 Notably, reduced KGDHC activity within the mitochondrial respiratory chain is an early pathological hallmark of PD. Impaired mitochondrial glutamate metabolism in astrocytes disrupts glutamate clearance and exacerbates excitotoxicity, while concurrent energy deficiency and excessive ROS production further increase neuronal vulnerability to both glutamate and oxidative stress.^89–94 Beyond glutamate metabolism, mitochondrial endoplasmic reticulum (ER) coupling via mitochondria-associated membranes (MAMs) is critical for Ca²⁺ homeostasis in astrocytes. MAMs mediate rapid exchange of Ca²⁺ and lipids between mitochondria and the ER.⁹⁵ As the major intracellular reservoir for Ca²⁺, the ER releases Ca²⁺ via 1,4,5-trisphosphate(IP₃) receptors.⁹⁶ Then, mitochondria rapidly sequester cytosolic Ca²⁺ by the mitochondrial calcium uniporter (MCU) and outer membrane channels.⁹⁷ This Ca²⁺ uptake activates TCA cycle and OXPHOS, boosting ATP production.⁸⁰ In PD, sustained extracellular Ca²⁺ influx coupled with mitochondrial Ca²⁺ overload disrupt this balance, driving neurodegenerative pathology.⁹⁸ Astrocytic mitochondria regulates intracellular Ca²⁺; their dysfunction slows Ca²⁺ clearance and accelerates Ca²⁺ wave propagation, impairing negative-feedback control of Ca²⁺ signals.^80,99

Targeting mitochondrial Ca²⁺ homeostasis and related pathways has emerged as a promising therapeutic strategy for PD. Recent preclinical investigations have explored the therapeutic potential of modulating mitochondrial dynamics, particularly the mitofusin-2 signaling pathway, to mitigate astrocytic senescence in PD mouse models.¹⁰⁰ Furthermore, the anti-diabetic drug metformin has shown efficacy by restoring mitochondrial function, reducing the release of mitochondrial DNA (mtDNA), and inhibiting the cGAS-STING pathway.^101,102 These pharmacological effects collectively inhibit astrocyte senescence and may delay PD pathological progression while mitigating the pathological damage. In summary, astrocytic mitochondrial dysfunction drives PD pathogenesis by disrupting redox homeostasis, exacerbating glutamate excitotoxicity, and dysregulated calcium homeostasis. Accordingly, mechanism-based studies of astrocytic mitochondria represents a key frontier for therapy and interventions in PD. Although multiple mitochondrial-targeted agents exert robust protective effects in preclinical models, most candidates fail to achieve satisfactory clinical efficacy, presumably due to complex human astrocyte heterogeneity unreflected in existing animal systems (Figure 2).

Figure 2.

Astrocytic mitochondrial dysfunction in PD. Mutations of PD-causative genes (PINK1, PRKN, DJ-1, LRRK2) together with environmental insults damage astrocytic mitochondrial integrity. Such injuries impair mitophagy, electron transport chain and oxidative phosphorylation (OXPHOS), and disrupt mitochondria-associated membranes (MAMs) contact between mitochondria and endoplasmic reticulum. These metabolic abnormalities lead to insufficient ATP synthesis, excess reactive oxygen species production and disordered intracellular Ca²⁺ homeostasis, further disrupting glutamate metabolism and aggravating excitotoxic neuronal damage. Meanwhile, persistent activation of the cGAS–STING inflammatory cascade drives astrocyte transformation from neuroprotective cells into pro-inflammatory and neurotoxic effectors.

Abbreviations: OXPHOS, oxidative phosphorylation; MAMs, mitochondria-associated membranes; KGDHC, α-ketoglutarate dehydrogenase complex; GDH, glutamate dehydrogenase.

Astrocyte-Mediated Neuroinflammation: A Pivotal Role in Parkinson’s Disease

Neuroinflammation driven by reactive astrocytes emerges as another core pathological mechanism in PD. It represents a fundamental host response to injury or pathological stimuli, initially acting to clear debris, eliminate pathogens, and promote tissue repair.^103,104 Acute neuroinflammation is protective, while chronic dysregulated inflammation drives neurodegeneration.¹⁰⁵ Within the CNS, neuroinflammation involves resident glia (microglia, astrocytes) and recruited peripheral immune cells, releasing cytokines, chemokines, and ROS that exert both protective and toxic effects.^106–108 Chronic neuroinflammation contributes to Alzheimer’s disease,¹⁰⁹ PD,¹¹⁰ multiple sclerosis,^111,112 and traumatic brain injury.^107,113 Studies in PD patients show altered inflammatory markers and immune cells in peripheral blood and cerebrospinal fluid, which both trigger and amplify neuroinflammation, accelerating neurodegenerative process.¹¹⁴ PD pathogenesis involves both central and peripheral inflammation; central inflammation contains the microglia, astrocytes, and T cells.¹¹⁵ Although neuroinflammation is a key driver of PD, the underlying mechanisms of glial cell subpopulations—namely microglia and astrocytes—and their roles in PD onset and progression remain unclear. Among these glial populations, astrocyte-mediated neuroinflammation has garnered increasing attention for its critical role in neurodegenerative diseases. Mounting evidence links persistent or dysregulated astrocyte-driven neuroinflammation to the pathogenesis of various neurological disorders, such as Alzheimer’s disease, PD,¹¹⁶ and multiple sclerosis.^111,112 While astrocyte-mediated neuroinflammation plays a pivotal role in the pathogenesis of PD, the precise mechanisms remain incompletely understood and are under active research.^117,118 Astrocytes exhibit a broad functional spectrum, ranging from a neurotoxic (pro-inflammatory) state to a neuroprotective (immunoregulatory) one. While astrocytes are a source of multiple pro-inflammatory factors such as TNF-α, IL-1α, IL-1β, and nitric oxide (NO),^119,120 their homeostatic anti-inflammatory properties predominate under physiological conditions.¹²¹ Astrocytes also increase the production of anti-inflammatory factors, including glutathione (GSH), ascorbic acid, glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF), thereby strengthening neuronal survival and promoting tissue repair.¹²² Specifically, they are capable of producing GSH to mitigate oxidative stress, thereby helping to counteract neurodegeneration driven by ROS.^123,124 Besides, they maintain cerebral homeostasis through upregulating specific channels to clear potassium and glutamate ions from compromised neurons.¹²⁵ However, astrocytes are recognized to exhibit a spectrum of reactive states that depend on the type and stage of the neurodegenerative disease and regional location.^119,126 Moreover, the phenotypic shift in astrocytes, its loss of neuroprotective function, and its acquirement of neurotoxic function are complex and likely differ with the progression and severity of the neurodegenerative disease. They should be regarded as being on a spectrum rather than two distinct groups. Consequently, the heterogeneity of reactive astrocytes warrants further investigation.¹¹⁹ This complexity might be the reason why anti-inflammatory drug trials have so far failed to demonstrate significant therapeutic efficacy.

In the pathological context of PD, the functional transformation of astrocytes is driven by altered expression of disease-related genes and toxic protein stimulation. Research has shown that several genes, including PARK2, PARK7, and PINK1, are significantly upregulated in this process.¹²⁷ In individuals with PD, reactive astrocytes exhibit an upregulation in the expression of lipocalin-2 (LCN2)—a molecule produced by these cells under inflammatory conditions. The released LCN2 subsequently promotes astrocytic morphological transformation, apoptosis, and migration.¹²⁸ Furthermore, astrocytes exhibit regional heterogeneity, demonstrating marked morphological differences between brain regions such as the striatum and hippocampus,^129,130 with an age-dependent decline in functional capacity.¹³¹ These alterations encompass electrophysiological properties, astrocyte-synapse proximity, and Ca²⁺ signaling.¹³² Such differences may underlie the region-specific susceptibility to damage observed in PD.¹³³ Notably, pathological α-Syn acts as a crucial trigger for astrocytic inflammation in a concentration-dependent manner. Studies indicate that exposure to elevated levels of extracellular α-Syn can induce an inflammatory response in primary cultured astrocytes.¹³⁴ Excessive extracellular and neuron-derived α-Syn accumulates in astrocytes, When α-Syn crosses a specific threshold, it induces neuroinflammation, setting in motion pathology linked to PD. Astrocytes that have accumulated neuron-derived α-Syn can induce the production of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α) and chemokines capable of activating microglia^135–137 (Figure 3).

Figure 3.

Astrocyte-mediated neuroinflammation in PD. Pathological α-Syn facilitates the activation of resting astrocytes and microglia, and reciprocal activation between the two glial populations (↑ denotes elevated secretion of pro-inflammatory cytokines; ↓ indicates decreased synthesis of endogenous protective molecules including glutathione and metallothionein) amplifies inflammatory cascades, disrupts blood-brain barrier (BBB) integrity, and promotes peripheral immune cell infiltration, ultimately resulting in progressive dopaminergic neuronal loss and degeneration.

Abbreviations: α-Syn, α-Synuclein; TNF-α, tumor necrosis factor alpha; IL-1α, interleukin-1 alpha; IL-1β, interleukin-1 beta; IL-6, interleukin-6; C1q, complement component 1q; BBB, blood-brain barrier; Glu, glutamate.

These mediators induce astrocyte dysfunction, thereby driving the progression and pathogenesis of PD. Furthermore, astrocytes act as a key amplifier of neuroinflammation. They are activated by pro-inflammatory cytokines including IL-1α, TNF-α, and complement component 1q (C1q), as well as mitochondrial fragments released by activated microglia.^138,139 Pathological α-Syn can also induce microglial activation, which subsequently triggers the transformation of astrocytes into a neurotoxic reactive state through IL-1α and TNF-α secretion.¹⁴⁰ Therefore, astrocytes and microglia are locked in a dynamic interplay, continuously regulating one another’s functional activities. While astrocytes respond to inflammation signals by modulating microglial activation, they may also react to inflammation elicited by microglial activity, exhibiting neurotoxic rather than neurotrophic properties. In the experiment of monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), astrocytic interferon(IFN)-γ receptor expression was upregulated, along with increased TNF-α immunoreactivity in astrocytes.¹⁴¹ This suggests that excessive astrocyte activation drives PD progression. In a separate investigation, astrocytes, derived from PD patient-induced pluripotent stem cells and containing α-Syn aggregates, when exposed to inflammatory stimuli, entered a hyperreactive state and secreted elevated levels of pro-inflammatory cytokines including IL-6 and CCL-5.¹⁴² Upregulated cytokines, chemokines, and ROS are typical hallmarks of reactive astrocytes in PD.¹⁴³ The oxidative stress and excitotoxicity linked to astrocyte-driven inflammation directly impair dopaminergic integrity and function, ultimately driving their gradual demise. Furthermore, the activation of astrocytes can lead to the recruitment and activation of other immune cells, such as microglia, thereby amplifying the inflammatory response within the brain.¹⁴⁴ The sustained astrocyte activation and the persistent inflammation may disrupt brain homeostasis and worsen PD-related pathological changes.^144,145 This neuroinflammatory cascade can trigger a vicious cycle, wherein ongoing dopaminergic neuron damage promotes the release of additional inflammatory mediators, which in turn amplifies the inflammatory response and drives further neurodegeneration.^47,146 Alongside neuroinflammation, BBB disruption is closely linked to PD progression. Researches have revealed that the BBB in PD patients exhibits increased leakiness and permeability in various basal ganglia regions, accompanied by cerebral microhemorrhages and systemic dysfunction of the BBB transporter system.^147–150 Astrocytes tightly surround cerebral endothelial cells and release regulatory factors such as transforming growth factor-α (TGF-α) and GDNF. These molecules stabilize endothelial tight junctions and maintain BBB integrity.¹⁵¹ They can also modulate cerebral microvascular permeability through astrocyte-endothelial communication.¹⁵² Additionally, astrocytes can produce vascular endothelial growth factor-A,¹⁵³ a critical regulator of BBB permeability, which then activates endothelial nitric oxide synthase in endothelial cells and downregulates the expression of occludin and claudin 5.¹⁵⁴ Reactive astrocytes can compromise the BBB and facilitate infiltration of peripheral immune cells, which further exacerbates chronic neuroinflammation and PD pathology.^144,155 Hence, astrocytes function as “gatekeepers” to prevent peripheral immune cell infiltration into brain. The observed elevation in BBB permeability in PD patients may be associated with impaired astrocyte-endothelial communication. In addition, fibrillar α-Syn disrupts the integrity of brain endothelial barriers.¹⁵⁶ It promotes inflammatory cytokines release from pericytes, which also contributes to BBB leakage.¹⁵⁷ Notably, astrocytic endfeet-expressed aquaporin-4 (AQP4), a key transmembrane water transport protein closely involved in maintaining BBB microenvironmental homeostasis, also critically modulates PD pathological progression.¹⁵⁸ While the molecular mechanisms by which AQP4 regulates PD pathogenesis remain poorly elucidated, existing animal evidence confirms that AQP4-deficiency exacerbates PD-like neuropathology upon MPTP challenge. Mechanistically, the loss of AQP4 impairs astrocytic transforming growth factor-β1 (TGF-β1) secretion, decreases this anti-inflammatory cytokine, and further promotes excessive astrocytosis and microgliosis. This ultimately elevates midbrain pro-inflammatory IL-1β and TNF-α levels, aggravates neuroinflammation, and increases dopaminergic neuron loss.¹¹⁸

Growing evidence highlights that astrocytes exert complex and multifaceted effects throughout PD-related neuroinflammation.¹⁵⁹ The diverse functional astrocytes reflect the intricate nature of PD pathogenesis. Clarifying the regulatory mechanisms of astrocyte activation is therefore essential for developing targeted therapeutic strategies.^155,160 Current studies cannot fully unify the classification criteria of reactive astrocyte subtypes, which partly accounts for the inconsistent efficacy of anti-inflammatory therapies across different PD clinical cohorts.

Oxidative Stress Imbalance in Astrocytes: A Key Pathological Axis in Parkinson’s Disease

Astrocyte-mediated neuroinflammation not only plays a central role in the onset and progression of PD but also closely interacts with intra-and extracellular redox imbalance. Oxidative stress refers to a disruption of the dynamic equilibrium between oxidants and antioxidants, in which the oxidant overload overwhelms endogenous defense systems. As the major intracellular oxidant molecule, ROS are physiological by-products of cellular metabolism and participate in signal transduction and immune regulation under physiological concentrations.¹⁶¹ Excessive ROS derived from neuroinflammation, glial activation, mitochondrial dysfunction, and metal dyshomeostasis can induce oxidative stress when production surpasses the scavenging capacity of antioxidant systems including glutathione, superoxide dismutase, and catalase.¹⁶² Excess ROS attack and damage proteins, lipids, and DNA, thereby compromising cellular structure and ultimately inducing cell death.¹⁶³ This oxidative injury is strongly linked to the pathogenesis and progression of various diseases, including neurodegenerative disorders.¹⁶⁴ Recent research has revealed that astrocytes, as the predominant glial cells of CNS, play a significant dual role in modulating oxidative stress in PD.¹⁶⁵ Under physiological conditions, astrocytes maintain redox homeostasis and neuronal survival via GSH synthesis, glutamate clearance to alleviate excitotoxicity, and Nrf2–ARE antioxidant pathway activation.¹⁶⁶ This neuroprotective function is particularly critical at early PD stages, enabling astrocytes to counteract excess oxidative load and support neuronal survival.⁵⁷ Cumulative evidence confirms a reciprocal pathological linkage between chronic neuroinflammation and astrocytic oxidative stress, jointly forming a self-amplifying vicious cycle accelerating PD deterioration. Upon persistent inflammatory stimulation, pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) secreted by damaged neurons and activated microglia drive resting astrocytes toward the neurotoxic A1 state.¹⁶⁷ A1 astrocytes upregulate NOX family enzymes and iNOS alongside overactivated NF-κB signaling, boosting intracellular ROS and reactive nitrogen species (RNS) accumulation while disrupting astrocytic mitochondrial integrity and endogenous antioxidant capacity.¹⁶⁸ These changes further stimulate the release of inflammatory and neurotoxic mediators, thereby exacerbating local inflammation and oxidative stress.¹⁴⁵ The intrinsic cellular antioxidant defense system is essential for counterbalancing elevated ROS production, with the Nrf2–ARE signaling pathway serving as its central regulatory axis. Physiologically, Nrf2 dissociates from Keap1 and translocates into the nucleus to induce glutamate-cysteine ligase, glutathione synthetase and HO-1 expression, facilitating GSH biosynthesis and sustains ROS homeostasis.¹⁶⁹ In PD pathological contexts, inflammation-derived oxidative stress suppresses Nrf2 transcriptional activity, reducing GSH synthesis and astrocytic metabolic homeostasis.^145,170 As the primary non-enzymatic antioxidant in astrocytes, GSH depletion not only lowers intrinsic ROS resistance of astrocytes but also weakens GSH supply to adjacent neurons, rendering neurons more vulnerable to oxidative stress.^37,145,160 Collectively, disrupted redox balance switches astrocytes from neuroprotective to pro-pathological reactive status characterized by robust ROS overproduction and collapsed antioxidant defenses. Beyond intracellular metabolic disturbance, sustained oxidative stress in astrocytes triggers multi-targeted pathological damage across the neurovascular unit. Excess ROS and pro-inflammatory factors secreted by chronically stimulated astrocytes impair their metabolic support capacity and compromise the survival and function of substantia nigra dopaminergic neurons.³⁷ Accumulated pathological stimuli remodel astrocytic structure and function in PD brain, accompanied by elevated expression of canonical reactive astrocyte markers GFAP and S100B, indicative of aberrant astrocyte overactivation.^59,171 Hyperactivated astrocytes construct a pro-oxidative and pro-inflammatory microenvironment to aggravate neuronal damage.¹⁷² Meanwhile, impaired glutamate clearance leads to synaptic glutamate accumulation, persistent NMDA receptors overactivation, cytoplasmic Ca²⁺ overload and consequent excitotoxic dopaminergic degeneration in the substantia nigra.^173,174 Apart from nigral lesions, oxidatively damaged astrocytes destroy neurovascular unit homeostasis and BBB integrity, hindering nutrient and oxygen transport toward neurons.^37,145,166 Moreover, astrocyte-derived oxidative and inflammatory factors impair microglial physiological function; dysfunctional microglia in turn produce extra ROS to feed forward inflammatory amplification.^159,166,175 In short, the bidirectional crosstalk between oxidative stress and neuroinflammation builds an “oxidative stress–inflammation” positive feedback loop: impaired astrocytes release cytotoxic substances to activate microglia and neurons, and activated glia further aggravate oxidative and inflammatory cascades to accelerate dopaminergic loss. Therefore, astrocytes function as both initiation sources and effector targets of oxidative stress and neuroinflammation, forming a core pathological axis driving PD advancement.

Multiple pathological contributors jointly trigger astrocytic redox imbalance, dominated by aberrant α-Syn aggregation, mitochondrial impairment, disrupted iron metabolism, persistent inflammation and defective antioxidant systems. Accumulating studies show that astrocytic oxidative stress in PD arises from the synergistic effect of these interrelated pathways. Notably, pathological α‑Syn aggregates serve as a primary initiator of astrocytic oxidative damage. Internalized α-Syn oligomers cannot be fully degraded within lysosomes, triggering lysosomal membrane permeabilization and subsequent ROS production.¹⁷⁶ Meanwhile, α-Syn oligomers directly bind astrocytic Toll-like receptors (TLRs) to activate NF-κB signaling and upregulate inflammation and oxidation‑related genes.¹⁷⁷ Downstream NF-κB activation drives transcription of the NADPH oxidase (NOX) family subunits (NOX2, NOX4), the major enzymatic source of intracellular ROS in astrocytes.¹⁷⁸ Once stimulated by pro‑inflammatory cytokines (TNF‑α, IL‑1β), activated NOX transfers electrons to oxygen to generate superoxide, and the resulting ROS further boosts NF‑κB activity, forming a self‑amplifying NF‑κB‑NOX‑ROS positive feedback loop.¹⁷⁹ In parallel, NF-κB also induces high expression of inducible nitric oxide synthase (iNOS) in astrocytes and microglia to sustain NO synthesis; NO reacts rapidly with superoxide (O₂⁻) to form cytotoxic peroxynitrite (ONOO⁻), which damages cellular biomolecules and increases dopaminergic neuronal vulnerability.^166,180,181 Apart from NOX‑derived oxidants, dysfunctional mitochondria constitute another dominant source of astrocytic ROS. In PD, impaired mitochondrial complex I disrupts the electron transport chain, elevates electron leakage and superoxide overproduction.¹⁸² This pathological change triggers a cascade of adverse outcomes: insufficient ATP generation, disrupted cytoplasmic Ca²⁺ homeostasis, and activation of pro‑apoptotic JNK/p38 MAPK pathways.⁸⁰ Damaged mitochondria further release mtDNA, cytochrome c, and other damage-associated molecular patterns (DAMPs) to activate adjacent glial and amplify neuroinflammation.¹⁸³ Such mitochondrial deficits stem from PD‑related gene mutations, environmental toxicants and intracellular α‑Syn deposition. Beyond mitochondrial defects that elevate ROS production, iron Iron metabolic disorder further exacerbates astrocytic oxidative stress downstream of α-Syn toxicity and mitochondrial injury. In PD astrocytes, abnormal expression of divalent metal transporter 1 (DMT1) and ferritin alongside excessive autophagy increases cytoplasmic labile Fe²⁺. Free ferrous iron catalyzes Fenton reactions with hydrogen peroxide to generate toxic hydroxyl radicals (·OH), which trigger lipid peroxidation, mitochondrial injury and potential astrocytic ferroptosis.^184,185 The excess oxidative radicals spread outward from damaged astrocytes and aggravate dopaminergic neurodegeneration.

Taken together, these cascading pathological events solidify the core oxidative stress‑inflammation vicious cycle mentioned above. Thus, targeting astrocytic oxidative stress provides promising therapeutic directions for PD treatment. Strategies aimed at enhancing astrocytic antioxidant defenses, restraining excessive inflammatory response and recovering mitochondrial function have become important research priorities for PD neuroprotection.^143,186 Despite confirmed antioxidative efficacy of Nrf2 agonists in preclinical research, inconsistent bioavailability in brain tissue limits their clinical transformation for PD treatment (Figure 4).

Figure 4.

Mechanistic diagram of the drivers of astrocytic oxidative stress in PD. This figure illustrates multiple interconnected pathological triggers that jointly induce astrocytic oxidative stress, including α-Syn aggregation, mitochondrial dysfunction, neuroinflammation, iron metabolic disturbance, and NADPH oxidase hyperactivation, alongside genetic and environmental contributors. These risk factors interact reciprocally to boost reactive oxygen species (ROS) and peroxynitrite (ONOO⁻) generation via Fenton reaction and NO-derived chemical reactions, establishing persistent oxidative damage inside astrocytes.

Abbreviations: α-Syn, α-Synuclein; ROS, reactive oxygen species; ONOO⁻, peroxynitrite; NADPH, nicotinamide adenine dinucleotide phosphate.

Conclusion

Astrocytes exert stage-dependent dual regulatory effects across the entire pathological cascade of PD, switching from homeostatic guardians to pathological accomplices as disease advances. As the most abundant glial population within the CNS, astrocytes maintain physiological homeostasis via neurotransmitter clearance, ion buffering, metabolic supply, synaptic modulation and BBB structural support under healthy conditions. In early PD stages, intact astrocytes defend neurons by clearing pathological α-Syn through UPS and ALP pathways, sustaining mitochondrial integrity, synthesizing antioxidant substances such as GSH and neurotrophic factors (GDNF, BDNF), and limiting excessive inflammatory burst to restrain neuronal injury. With persistent stimulation from aggregated α‑Syn, mitochondrial damage, sustained inflammation and disrupted iron metabolism, astrocytes undergo progressive functional remodeling and transform into pro‑toxic reactive states. Pathogenic α-Syn cannot be fully degraded by impaired astrocytic clearance systems and spreads bidirectionally between neurons and glia via endocytosis, TNTs and EVs to aggravate widespread protein pathology; meanwhile, accumulated α-Syn initiates NF-κB/NOX cascade activation, triggering robust neuroinflammation and excessive ROS production. Abnormalities of PD‑related genes (PINK1, PARK2, DJ‑1, etc.) further destroy astrocytic mitochondrial structure and function, hindering ATP generation, disturbing Ca²⁺ homeostasis, and exacerbating glutamate‑mediated excitotoxicity. In addition, dysregulated iron metabolism boosts Fenton reaction‑derived toxic radicals and aggravates astrocytic oxidative damage. Collectively, inflammatory mediators, excessive ROS, and impaired BBB function jointly construct a self‑reinforcing vicious cycle consisting of “α‑Syn aggregation–mitochondrial lesion–neuroinflammation–oxidative stress”, which continuously promotes progressive loss of nigral dopaminergic neurons.

Different from previous reviews focusing merely on neuronal degeneration or a single pathological pathway, this review systematically integrates four core pathological axes centered on astrocyte dysfunction: abnormal α-Syn trafficking, mitochondrial impairment, reactive neuroinflammation and redox imbalance, and elaborates their mutual crosstalk to interpret astrocyte stage-dependent dual property in PD pathogenesis. Such integrated framework clarifies why astrocyte-targeted intervention is a promising therapeutic direction against PD. Accordingly, based on current research progress, prospective therapeutic strategies mainly include four directions: activating the Nrf2-ARE pathway to elevate astrocytic antioxidant capacity, inhibiting NF-κB/JAK/STAT3 inflammatory cascades to block glial overactivation, improving lysosomal/proteasome function to restrict α-Syn intercellular propagation, and supplementing neurotrophic factors to recover astrocytic homeostatic secretion.

Nevertheless, numerous unresolved issues still restrict the translational application of these astrocyte-targeted therapies. Hence, future research needs to resolve several pending controversies in this field: clarifying spatiotemporal heterogeneous characteristics of distinct astrocyte subsets in different PD brain regions, revealing the concrete upstream signals driving astrocyte state conversion, and exploring in vivo dynamic interactions among astrocytes, microglia, and peripheral immune cells with the aid of single-cell transcriptomics, spatial omics and multimodal in vivo imaging. Deep decipherment of above questions will facilitate the development of early diagnostic biomarkers and novel disease-modified therapies targeting astrocytes for PD.

Disclosure

The authors report no conflicts of interest in this work.