Functional characteristics, intercellular interactions and pathophysiological associations of astrocytes in Parkinson’s disease

Introduction

Parkinson’s disease (PD) predominantly affects middle-aged and elderly individuals and is characterized by movement-related disorders. These typically manifest as resting tremors, bradykinesia, and impaired postural balance. The underlying cause of these motor symptoms is the degeneration of neurons in specific brain regions, results in reduced dopamine production (Wang et al., 2023). Dopamine is a critical neurotransmitter.

Astrocytes are the most abundant glial cells in the brain. An increasing body of research suggests that astrocytes carry out a wide array of essential functions. These include regulating ionic homeostasis and secreting neurotrophic factors, both of which are critical for maintaining the physiological environment of the brain and supporting neuronal health (Pehar et al., 2004). Furthermore, certain genetic mutations associated with PD are believed to impair astrocyte function (Booth, Hirst & Wade-Martins, 2017). This review aims to examine the role of astrocytes in PD, focusing on the mechanisms underlying their dysfunction and the resulting pathological consequences (Fig. 1).

Search methodology

Several key steps were undertaken to ensure that the literature review was both comprehensive and unbiased (Fig. 2). First, an extensive search was conducted across multiple academic databases (including PubMed, Scopus and Web of Science) to identify relevant trials, guidelines and research reports. The search terms included “Parkinson’s disease,” “astrocyte,” “brain,” “signaling mechanisms,” and “α-synuclein” to capture a broad range of relevant sources. Literature that did not meet the inclusion criteria was excluded, including non-peer-reviewed publications, studies unrelated to astrocytes, non-English articles, and those focused primarily on Alzheimer’s disease. Following this initial screening, selected articles were critically evaluated for their relevance and methodological quality. To minimize selection bias, studies from various disciplines and countries were included, encompassing both theoretical and applied perspectives. Articles were chosen based on their focus on the interaction between PD and astrocytes, while those with irrelevant content or insufficient experimental rigor were excluded. Efforts were also made to incorporate both foundational and recent publications to ensure a balanced and comprehensive overview. Additionally, a snowballing technique was employed by reviewing the reference lists of identified articles to locate further relevant publications that may have been missed during the initial database search, thereby enhancing the overall depth and breadth of the review.

Astrocytes and the blood-brain barrier

The blood-brain barrier (BBB) is a critical interface between the cerebral parenchyma and the systemic circulation. It is regulated by a complex network comprising astrocytes, endothelial cells, and specialized pericytes, which together constitute the neurovascular units. This highly selective barrier tightly governs molecular trafficking, allowing the controlled influx of essential substances required for neural homeostasis while effectively restricting the entry of potentially harmful substances, thereby safeguarding neural tissue from toxic insults (Iadecola, 2017). Accumulating evidence has shown that astrocytes play a pivotal role in enhancing the functional integrity of the BBB (Fig. 1). Notably, in co-culture systems with endothelial cells, astrocytes have been demonstrated to induce the transdifferentiation of non-neurovascular endothelial cells into a brain-specific phenotype, thereby giving them BBB-like characteristics (Hayashi et al., 1997).

Apolipoprotein E (APOE), which is endogenously synthesized by astrocytes, is a multifunctional secreted macromolecule with a plethora of functions integral to maintaining cerebrovascular homeostasis. Under physiological conditions, APOE plays a critical role in preserving, the structural integrity of the BBB, primarily by modulating intercellular and extracellular interactions within the neurovascular unit. It is hypothesized that APOE proteins contribute to the stability of tight junctions in BBB endothelial cells. They achieve this by precisely regulating the complex metabolic processes associated with extracellular matrix components. Specifically, APOE has been implicated in the regulation of key matrix proteins such as collagen and laminin, which are essential for maintaining tight junction integrity. In humans, the APOE4 allele has been associated with increased BBB permeability (Jackson et al., 2022). Experimental studies using APOE4-transgenic mice have demonstrated that this allele induces tight junction disruption, abnormal overexpression of matrix metalloproteinase 9 (MMP9), and reduced vascular coverage of terminal peduncles. Collectively, these changes result in elevated BBB permeability, allowing peripheral inflammatory cytokines and immune cells to infiltrate the brain parenchyma, thereby exacerbating neuroinflammation and neuronal injury. Notably, astrocyte-specific deletion of APOE4 has been shown to reverse these pathological phenotypes (Jackson et al., 2022). These findings are particularly relevant for understanding the vascular dysfunctions associated with APOE4 in the context of PD, offering novel insights into the disease’s underlying mechanisms. Further studies by Cooper et al. (2021) demonstrated that APOE4 has the highest binding affinity for low-density lipoprotein receptor-related protein 1 (LRP1), and that its lipidation state in the vascular microenvironment may influence its activity. Interestingly, the detrimental effects of astrocyte-derived APOE4 on BBB integrity may also occur via an LRP1-independent pathway, potentially involving alternative signaling mechanisms that activate MMP9.

Astrocytes can precisely regulate the functional activity of tight junction (TJ) proteins within the cytoplasmic environment of endothelial cells by secreting a diverse array of growth factors (Pivoriunas & Verkhratsky, 2021). The interaction between endothelial cells and astrocytes is therefore essential for maintaining the structural and functional integrity of the BBB. TJ proteins are critical for preventing transcellular diffusion of molecules through intercellular spaces and play a key role in defining the apical and basolateral domains of the plasma membrane, thereby supporting the establishment and maintenance of endothelial cell polarity (Wolburg & Lippoldt, 2002). Proper regulation of BBB permeability is vital for neuronal survival, as the barrier’s selective properties effectively prevent harmful substances from entering the brain, thus preserving the neural microenvironment. Astrocytes contribute to this regulatory network by releasing cytokines and signaling molecules that finely modulate TJ protein expression, ensuring the continued structural and functional integrity of the BBB. Additionally, astrocytes are involved in maintaining water and potassium ion homeostasis. Their perivascular end-feet extensively cover capillary surfaces and fulfill a variety of essential functions linked to BBB physiology. Notably, these end-feet express aquaporin (AQP) channels (Lanciotti et al., 2013), In humans, aquaporins are classified as AQP1 and AQP4, with AQP4 being predominantly expressed in the perivascular astrocytic end-feet (Lanciotti et al., 2013). Reduced AQP4 expression has been associated with disrupted potassium (K⁺) homeostasis, indicating its key role in maintaining ionic balance (Binder et al., 2006). Furthermore, astrocytes secrete antioxidants, particularly glutathion, which are thought to influence BBB permeability. Glutathione protects neurons from neurotoxic damage by reducing the ability of harmful molecules to penetrate the brain (Agarwal & Shukla, 1999).

In the cerebral parenchyma of patients with PD, the integrity of BBB is compromised. Subtle disruptions have been identified in brain regions critical to PD pathophysiology, including the substantia nigra, white matter tracts, and posterior cortical areas (Aflaki et al., 2020). These findings suggest a complex association between BBB breakdown and PD development. As previously discussed, astrocyte dysfunction is a key contributor to BBB disruption. In the healthy cerebral cortex, astrocytes promote the secretion of TJ proteins through the release of cytokines. However, under the pathological conditions of PD, reactive astrocytes exhibit significantly reduced expression of growth factors (Pehar et al., 2004). This decline in growth factor expression leads to a corresponding reduction in TJ protein production. The resultant TJ protein deficiency increases BBB permeability, rendering the brain more vulnerable to environmental toxins and harmful substances. These external insults can initiate a cascade of deleterious events that ultimately lead to neuronal death.

Conventional therapeutic approaches for PD, such as deep-brain electrical stimulation and dopamine replacement therapy, provide symptomatic relief but do not offer a cure (Khor et al., 2024). Recently, bioengineered exosomes have emerged as a promising therapeutic strategy due to their ability to cross the BBB. Their innate permeability, coupled with excellent biocompatibility, makes them ideal carriers for delivering therapeutic agents. Consequently, bioengineered exosomes hold considerable potential for the effective treatment of PD, representing a novel and potentially more efficient approach to managing this neurodegenerative disorder (Afzal et al., 2025).

Astrocytes and alpha-synuclein

Alpha-Synuclein (α-syn) is a highly dynamic intracellular protein that normally exists in monomeric or multimeric forms (Afzal et al., 2025; Dettmer, 2018). However, when aggregated, α-syn becomes neurotoxic (Stefanis, 2012). Extracellular α-syn can be internalized by neighboring neurons, potentially propagating pathology (Xie et al., 2022). Astrocytes play a protective role by attenuating neuronal α-syn pathology through uptake and regulation of protein homeostasis mechanisms associated with the formation, trafficking, depolymerization, and clearance of toxic α-syn aggregates, as demonstrated in various in vitro and in vivo models of α-synucleinopathies (Yang et al., 2022). Astrocytes also reduce neurotoxicity by phagocytosing extracellular α-syn (Hua et al., 2019; Yang et al., 2022), and secrete molecules capable of degrading extracellular α-syn. Notably, protein disulfide isomerase, a thiol-disulfide oxidoreductase highly expressed in astrocytes, has been shown to inhibit α-syn fibrillation (Serrano et al., 2020). However, excessive α-syn can induce astrocytic activation and transformation into a pro-inflammatory phenotype, which negatively affects neuronal survival (Chou et al., 2021). In PD, α-syn misfolds and assembles into oligomers and fibrils that accumulate within neurons and glial cells, eventually forming Lewy bodies—a pathological hallmark of the disease. These aggregates activate astrocytes, causing significant morphological and functional changes. Activated astrocytes release inflammatory cytokines and oxidative stress-related molecules, which, through a feedback mechanism, promote further α-syn misfolding and aggregation. This establishes a self-amplifying cycle (da Fonseca, Villar-Pique & Outeiro, 2015; Parmar, 2022), that intensifies neuronal damage, accelerates PD progression, and worsens clinical outcomes (Yan et al., 2024).

Given this duality, reactive astrocytes cannot be regarded solely as protective; under certain conditions, they may exert neurodegenerative effects. Therefore, therapeutic strategies involving astrocytes must carefully consider this complexity (Wang, Sun & Dettmer, 2023). Additionally, intracellular pathological α-syn can be secreted into the extracellular environment, activating neighboring neurons and glial cells (He et al., 2024). This creates a microenvironment persistently influenced by α-syn, contributing to chronic neuroinflammation and neurodegeneration. Thus, α-syn functions as a critical link between inflammatory and degenerative processes in PD (Serrano et al., 2020).

Glutamate metabolism in astrocytes

Glutamate is a major excitatory neurotransmitter in the brain (Fig. 3). However, excessive glutamate accumulation in the synaptic cleft is neurotoxic due to overstimulation of N-methyl-D-aspartate (NMDA) receptors, leading to elevated intracellular calcium, activation of cell death signaling pathways, and ultimately, neuronal necrosis and apoptosis (Shen et al., 2022). Glutamate excitotoxicity is a key contributor to dopaminergic neuron degeneration in PD. In PD, dysfunction or loss of glutamate dehydrogenase (GDH)—a critical enzyme in glutamate metabolism—has been observed. GDH plays a central role in bridging the GABA–glutamine cycle with the tricarboxylic acid (TCA) cycle. As the brain is the most energy-demanding organ, and neurons rely heavily on oxidative metabolism, GDH is essential for sustaining energy production, especially under conditions of increased demand. It facilitates glutamate metabolism and regulates mitochondrial respiratory activity, thus supporting neuronal viability and neuroplasticity (Michaelis et al., 2011).

Astrocytes play a crucial role in maintaining the brain’s chemical balance by efficiently removing excess glutamate from the extracellular space. This function is primarily mediated by excitatory amino acid transporters (EAATs) located on the astrocytic membrane. By regulating extracellular glutamate levels, astrocytes prevent glutamate excitotoxicity—a pathological condition in which excessive glutamate overstimulates receptors, leading to neuronal damage and death. This regulatory mechanism is essential for preserving neuronal integrity and ensuring that glutamate concentrations remain within a physiological range, thereby supporting normal synaptic transmission and neural function (Cuellar-Santoyo et al., 2022).

To further investigate the neuroprotective role of astrocytes in mitigating glutamate toxicity, Rosenberg & Aizenman (1989) demonstrated that cortical neurons cultured in astrocyte-poor media were approximately 100-fold more susceptible to prolonged glutamate exposure than those cultured in astrocyte-rich conditions. This finding highlights the indispensable role of astrocytes in protecting neurons from excitotoxic damage and maintaining the physiological stability of the nervous system (Rosenberg & Aizenman, 1989). Astrocytes also participate in neurotransmitter recycling and energy metabolism through dual metabolic pathways. Through the GABA–glutamine–glutamate (GGG) cycle, astrocytes convert absorbed glutamate or GABA into glutamine, which is subsequently shuttled back to neurons. Alternatively, these neurotransmitters can be metabolized into α-ketoglutarate (α-KG) via the TCA cycle, contributing to ATP synthesis. This dual role highlights the capacity of astrocytes to regulate extracellular neurotransmitter levels while simultaneously supporting the brain’s high energy demands (Zhou & Danbolt, 2014). The GGG cycle maintains a dynamic balance of glutamate, glutamine, and GABA between astrocytes and neurons. Specifically, glutamate and GABA are transported from neurons to astrocytes, while glutamine is returned to neurons, ensuring proper synaptic communication and neural function (Walls et al., 2015). Disruption of the GGG cycle has been implicated in various pathological conditions, including neurodevelopmental and neurodegenerative disorders such as PD and Alzheimer’s disease, as well as psychiatric and cognitive impairments. Given its central role in neurotransmitter regulation, GGG cycle dysregulation can have widespread consequences for brain function and systemic health (Lander et al., 2020; Rappeneau et al., 2016). Emerging evidence suggests that glutamatergic astrocytes, despite being relatively rare, play a pivotal role in modulating the integrity of cortico-hippocampal and nigrostriatal circuits under both physiological and pathological conditions. In PD, the subthalamic nucleus, a key node in the basal ganglia–thalamo–cortical loop, exhibits pathological hyperactivation that is closely linked to glutamatergic astrocyte dysfunction. This connection highlights a critical role for glutamatergic astrocytes in maintaining circuit homeostasis and positions them as promising therapeutic targets for PD. Harnessing the unique functional properties of these astrocytes may enable the development of novel interventions aimed at restoring disrupted neural connectivity and alleviating both motor and non-motor symptoms in PD (de Ceglia et al., 2023). Beyond glutamate regulation, astrocytes contribute to multiple aspects of brain metabolism, underscoring their broad influence on neural health and signaling. This includes key roles in fatty acid metabolism, which is integral to sustaining the physiological function of the nervous system.

Astrocytes and microglia: role of cells in PD

Role of astrocytes and oligodendrocytes in PD

Beta-glucocerebrosidase (GBA1) is a membrane-bound lysosomal enzyme, and the accumulation of its substrates in neurons has been associated with cognitive impairments, motor and coordination deficits, and psychiatric disorders (Orvisky et al., 2002; Schueler et al., 2003). This accumulation triggers neurotoxicity, astrocytic hyperplasia, and neuroinflammation in both human patients and mouse models, with evidence of astrocyte proliferation and heightened inflammatory responses (Farfel-Becker et al., 2014, 2011; Wong et al., 2004). Mutations in the GBA1 gene cause Gaucher’s disease (GD), a lysosomal storage disorder, and represent one of the most common genetic risk factors for PD, increasing the likelihood of PD onset by 20- to 30-fold (Stoker, Torsney & Barker, 2018). Approximately 20% of adults with GD, including those with type 1, develop PD-related symptoms later in life (Alaei et al., 2019). Recent experimental studies provide compelling evidence that glial β-glucocerebrosidase plays a central role in both GD and GBA1-associated PD. Specifically, depletion of β-glucocerebrosidase in astrocytes and microglia leads to lysosomal dysfunction, neuroinflammation, α-syn accumulation, and impaired communication with neurons, all of which contribute to disease pathogenesis (Aflaki et al., 2020; Boddupalli et al., 2022; Brunialti et al., 2021; Sanyal et al., 2020; Wang et al., 2022b).

Oligodendrocytes, a type of glial cell, primarily function to envelop axons in the central nervous system (CNS) and form insulating myelin sheaths (Duncan, Simkins & Emery, 2021). Abnormalities in oligodendrocyte function can lead to neuronal damage (Pandey et al., 2022). Although clinical studies suggest a potential role for oligodendrocytes in neurodegenerative processes, research on their involvement in GBA1-related disorders remains relatively limited. Myelin, a lipid-rich insulating membrane, facilitates the saltatory conduction of action potentials and provides structural protection to axons (Kuhn et al., 2019). Due to the biochemical complexity of myelin, oligodendrocytes require tightly regulated lipid synthesis and degradation pathways to ensure proper myelin formation and maintenance (Meschkat et al., 2022). In addition, they rely on specialized axon-glia communication pathways to deliver nutrients and organelles to distal regions of axons (Edgar et al., 2021).

Some studies have shown that oligodendrocyte impairments can lead to neurodegenerative features in mice, including axonal degeneration, microglial activation, astrocyte proliferation, and behavioral abnormalities. These findings suggest that oligodendrocytes play a significant role in neurodegeneration following the loss of β-glucocerebrosidase function, highlighting the critical contribution of oligodendrocyte dysfunction to the initiation and progression of GBA1-related neuropathology (Zhang et al., 2024).

PD has traditionally been considered a gray matter disorder; however, growing evidence supports the involvement of multiple glial cell types in the etiology of this synucleinopathy. Experimental studies have revealed significant effects on astrocytes, including impaired degradative capacity and dysfunctional inflammatory responses (Aflaki et al., 2020; Sanyal et al., 2020) In addition, microglia also exhibit compromised function in the context of PD, particularly due to defective β-glucocerebrosidase, which renders them unable to protect neurons from oxidative stress (Brunialti et al., 2021).

Astrocytes regulate iron death, copper death in PD

Ferroptosis, a recently recognized form of regulated cell death, is characterized by iron accumulation and lipid peroxidation, and it plays a significant role in the degeneration of dopaminergic neurons in PD. In the autonomic nervous system, ferroptosis may also affect the vagus and parasympathetic nerves within specific tissues, potentially leading to functional impairments (Zhang et al., 2022a). In multiple PD models, treatment with ferrostatin-1 (Fer-1), a classical ferroptosis inhibitor, has been shown to reverse cell death (Do Van et al., 2016; Mahoney-Sanchez et al., 2022; Sun et al., 2021). Ferritin, the primary iron-sequestering protein, plays a pivotal role in maintaining iron homeostasis and is localized in various intracellular compartments or secreted extracellularly. Studies have shown that in primary-cultured astrocytes, iron exposure leads to increased intracellular iron levels, which triggers compensatory upregulation of ferritin secretion to buffer extracellular iron (Wu et al., 2022). In co-culture systems of primary astrocytes and MES 23.5 dopaminergic cells, ferritin released by astrocytes was found to enter the dopaminergic cells and exert a protective effect. These findings suggest that under iron overload, astrocyte-mediated ferritin secretion may mitigate oxidative stress and ferroptosis in dopaminergic neurons, a key process implicated in PD pathogenesis (Zhang et al., 2022b). NADPH oxidase 4 (NOX4), a prominent member of the NOX family, is highly expressed in astrocytes in the CNS (Ma et al., 2017). NOX4 is expressed predominantly in astrocytes (Nayernia, Jaquet & Krause, 2014). NOX4 activation contributes to ferroptosis by inducing mitochondrial dysfunction in astrocytes (Wu et al., 2025), and elevated NOX4 levels can independently promote neuronal and astrocytic cell death (Park et al., 2021). Experimental evidence shows that NOX4 upregulation leads to mitochondrial dysfunction, initiating a cascade involving neuroinflammatory mediators such as osteopontin (OPN) and myeloperoxidase (MPO), which further promote astrocyte ferroptosis and accelerate PD progression (Boonpraman et al., 2023). With aging, astrocytes exhibit increased NOX activity and superoxide production, both of which contribute to PD pathogenesis (Chekol Abebe et al., 2022). Additionally, ionic imbalance in PD is thought to trigger ferroptotic cell damage in both neurons and oligodendrocytes. The presence of abnormal lipid-binding, disrupted redox balance, and elevated β-sheet-rich α-syn further supports the occurrence of ferroptosis in the PD microenvironment. These α-syn aggregates may interact with membrane lipids, compromise membrane integrity, and facilitate excessive Ca²⁺ influx into mitochondria, thereby enhancing ROS production and triggering ferroptosis (Fang et al., 2023). This cascade of events amplifies inflammatory responses and immune dysregulation, further exacerbating the neurodegenerative progression of PD (Zhang et al., 2024).

Copper-mediated cell death, also known as cuproptosis, is a recently identified form of regulated cell death that bears mechanistic similarity to ferroptosis. Copper, an essential trace element, functions as a critical enzymatic cofactor in oxidative metabolism, antioxidant defense, and neurotransmitter biosynthesis. In cuproptosis, copper ions directly bind to thioctylated moieties on proteins involved in the TCA cycle, leading to the abnormal aggregation of these proteins and the concurrent depletion of iron–sulfur cluster-containing proteins. This interaction induces a proteotoxic stress response that ultimately results in cell death (Tsvetkov et al., 2022). Copper is vital for numerous neuronal processes, including modulation of synaptic proteins and neurotransmitter receptors (Gaier, Eipper & Mains, 2013). However, in vitro studies have shown that high concentrations of copper can promote the formation of partially folded, aggregation-prone amyloidogenic proteins (Gromadzka et al., 2020). Mechanistically, copper dyshomeostasis has been linked to toxic effects, particularly through the promotion of oxidative stress (Giampietro et al., 2018). As a result, precise regulation of copper levels is essential in preventing neurodegenerative processes associated with PD. This understanding has inspired novel therapeutic approaches aimed at restoring copper balance, such as the use of copper chelators, which have been shown to mitigate α-syn oligomer-induced ROS production (Gromadzka et al., 2020; Deas et al., 2016). In parallel, mitochondrial dysfunction—a central feature of PD pathophysiology—continues to be a major focus of therapeutic exploration, with several strategies aimed at enhancing the clearance of damaged mitochondria (Malpartida et al., 2021). For instance, PARK2 knockout in homozygous human induced pluripotent stem cells has been associated with disrupted TCA cycle activity, mitochondrial ultrastructural abnormalities, and increased oxidative stress (Okarmus et al., 2021). These findings support a close association between copper toxicity and PD, although the precise molecular mechanisms remain to be elucidated. Emerging research into genetic regulators, including key genes and microRNAs, may help clarify the interplay between cuproptosis and PD. Given that both cuproptosis and ferroptosis involve mitochondrial dysfunction and excess acetyl-coenzyme A generation, it is plausible that these two pathways may be interrelated (Zhang et al., 2022a). Nevertheless, as both mechanisms are still in early stages of investigation, their specific contributions to PD pathology require further study.

Clinical management strategies in PD

PD is predominantly characterized by the degeneration of dopaminergic (DA) neurons. One proposed therapeutic strategy involves replacing these lost neurons. A promising approach entails the use of microRNA (miRNA) to reprogram midbrain astrocytes into DA neurons (Wei & Shetty, 2021). Studies have demonstrated the efficacy of this method in both in vivo and in vitro models (Ghasemi-Kasman et al., 2015). However, despite its therapeutic potential, this strategy has several limitations. Notably, astrocyte reprogramming does not address the persistent presence of α-syn, which can propagate between cells and potentially infect newly generated neurons. Additionally, for this approach to be effective, the reprogrammed neurons must successfully integrate into existing neural circuits. Furthermore, in vivo reprogramming could lead to the depletion of astrocytes, which are essential for maintaining brain homeostasis, thereby limiting the overall therapeutic benefit of this strategy.

Currently, bioengineered exosomes are under investigation as a novel therapeutic approach for PD. Their ability to cross the BBB and their inherent biocompatibility make them suitable vectors for delivering therapeutic agents. This is particularly relevant considering the multifaceted roles of astrocytes, microglia, and α-syn in PD pathophysiology (Wei & Shetty, 2021). Bioengineered exosomes may modulate astrocytic inflammatory responses through various mechanisms. They have the capacity to regulate microglial polarization, prevent microglial overactivation, influence signal transduction between oligodendrocytes and neurons, and support effective nerve impulse conduction (Afzal et al., 2025). Through the regulation of these glial functions, bioengineered exosomes offer a promising avenue for modulating disease progression in PD.

In summary, this review emphasizes the central roles of astrocytes in both brain homeostasis and PD pathology (Fig. 4). Healthy astrocytes promote neuronal survival by releasing neurotrophic factors, clearing extracellular α-syn, regulating glutamate and fatty acid metabolism, and preserving BBB integrity. In contrast, dysfunctional astrocytes contribute to disease progression and neurodegeneration, while also affecting interactions with neurons and other glial cells. Notably, treatments such as deep brain stimulation may potentially mitigate ferroptosis and cuproptosis. Given the abundance of astrocytes in the brain, a comprehensive understanding of their complex and dynamic roles is essential for advancing therapeutic strategies against neurodegenerative disorders.

Future prospects and limitations

Although current research has illuminated some aspects of the interactions between astrocytes and other glial and neuronal cell types in PD, many mechanistic details remain elusive. Future studies should aim to elucidate the fine-tuned regulatory mechanisms underlying intercellular signaling pathways. For instance, it is crucial to determine how astrocyte-derived cytokines and chemokines modulate microglial activation states and functional responses. Furthermore, understanding the specificity of cell–cell interactions across different brain regions is essential for explaining region-specific pathological changes observed in PD. Such insights could enable the development of highly targeted modulators to precisely intervene in disease processes.

In parallel, ferroptosis and cuproptosis have emerged as significant contributors to PD pathology. However, the underlying mechanisms remain incompletely defined. Future investigations should focus on delineating the specific regulatory pathways governing ferroptosis and cuproptosis in various brain cell types—particularly dopaminergic neurons and astrocytes—as well as their relationships with other forms of cell death, such as apoptosis and pyroptosis. These insights may facilitate the design of novel therapeutic agents capable of precisely modulating these pathways, thereby opening new directions for PD treatment.

Another critical limitation in the current field is the lack of standardized research methodologies. Disparities in experimental protocols, such as differences in cell culture conditions, animal models, and evaluation metrics, hamper direct comparisons and integration of findings across studies. This lack of uniform standards reduces both the reproducibility and translational potential of research outcomes. Addressing this issue by establishing unified experimental frameworks will be instrumental in accelerating progress and ensuring the clinical relevance of future discoveries.