Introduction

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective vulnerability of dopaminergic neurons in the midbrain substantia nigra pars compacta (SNpc) [1]. Degeneration of dopaminergic neurons in the SNpc that project to the striatum reduces dopamine input to the basal ganglia, resulting in motor symptoms such as bradykinesia and rigidity [2]. Another neuropathological feature of PD is the presence of Lewy bodies (LBs) and Lewy neurites (LNs), which are formed by abnormal deposition of α-synuclein (α-syn), dysmorphic organelles, vesicular structures, and lipids in the cytoplasm of neurons in several different brain regions [3, 4]. Although PD was initially described as a movement disorder closely related to dopaminergic neuron degeneration, other cell types throughout the central and peripheral autonomic nervous system are also involved. This may lead to various symptoms, including nonmotor hyposmia, sleep disorders, constipation, and cognitive and psychiatric symptoms such as dementia and depression [5].

Although most PD cases are sporadic, a substantial proportion of PD cases are attributed to variants or alterations in specific monogenic genes. To date, mutations in at least 20 genes have been identified to be responsible for PD [6]. Additionally, variants of these genes collectively play a role in the development of sporadic PD [7]. Intraneuronal protein aggregates consisting primarily of α-syn are found in most patients with PD. According to the findings of a large-scale genome-wide association study (GWAS), polymorphisms in noncoding regions of the α-syn gene, SNCA, are significant risk factors for idiopathic PD [8]. α-Syn can deviate from its native state, forming amyloid fibrils, ultimately resulting in the formation of cytoplasmic inclusions, which are associated with several neurodegenerative diseases, including PD [9, 10], dementia with Lewy bodies (DLB) [11, 12], and multiple system atrophy (MSA) [13, 14]. Various pathological α-syn aggregates can form from the same precursor protein, for instance, LBs in neurons [15] and GCIs (glial cytoplasmic inclusions) in glial cells [16], leading to the diverse clinical and pathological characteristics of α-synucleinopathies [17].

Microglia are the primary type of innate immune cells in the central nervous system (CNS), accounting for approximately 5–10% of all glial cells in the healthy human brain [18]. Mammalian microglia originate from myeloid precursor cells in yolk sac tissue before migrating to and colonizing the brain. In the CNS, microglia are considered to reach a stable state and are responsible for maintaining immune homeostasis and protecting the brain against diseases and pathogens [19]. α-Syn aggregation has been demonstrated to not only evoke the innate immune response but also recruit and activate the adaptive arms of the immune system in PD to promote neuroinflammation [20, 21], and microglial activation is the initial step in this process [22]. Additionally, microglial activation induced by inflammagen such as lipopolysaccharide (LPS), stimulates the aggregation of insoluble α-syn and exacerbates neuroinflammation [23, 24]. This implies that microglial activation and inflammation engage in a self-perpetuating cycle. Similar to macrophages, microglia play a crucial role in eliminating invading pathogenic bacteria, cell debris, and abnormal proteins from the CNS [25, 26]. Investigations involving positron emission tomography (PET) have revealed that microglia are activated in the brains of individuals with PD [27]. Recently, emerging evidence has suggested that microglia perform a variety of distinct roles, exhibiting a spectrum of phenotypes in the pathogenesis of PD. For example, under inflammatory conditions, microglia can secrete cytotoxic proinflammatory cytokines and directly promote dopaminergic neuron death; alternatively, activated microglia can scavenge debris and toxic metabolites from damaged neurons and other cells. Activated microglia can clear pathological α-syn through phagocytosis, and microglia activated by IL-6 may attenuate the number of α-syn inclusions in animal models [28]. Microglial phagocytosis can be selectively activated by the monomeric form of α-syn but is suppressed by aggregated α-syn and promotes α-syn-induced dopaminergic neurotoxicity, suggesting that microglia contribute to the pathological process of PD [29, 30]. In addition, several PD-related genes, such as leucine-rich repeat kinase 2 (LRRK2) and DJ-1, are expressed in microglia and regulate microglial clearance [31,32,33], suggesting that microglial phagocytosis contributes to the development and progression of PD pathology. These findings demonstrate that phagocytosis of α-syn cooperates with intracellular events involved in α-syn processing by microglia, which is involved in neuronal deposition, spreading, and disease progression. Therefore, elucidating the association between microglial activation and α-syn aggregation and propagation may provide insight into the pathological progression of PD, which is critical for develo** future therapies.

In this review, we summarize recent findings related to microglial activation and microglia-associated neuroinflammation that are relevant to α-syn aggregation and propagation. We focus our discussions on research developments related to cellular processes associated with inflammation, describing the current understanding of the connection between α-syn and the disruption of microglial homeostasis in the pathogenesis of PD. In addition, we also discuss current therapeutic approaches targeting microglia-mediated inflammation for preventing disease progression from the perspective of these new findings.

Structure and conformation of α-syn

The α-syn protein, encoded by the SNCA gene, is abundantly expressed in neuronal presynaptic terminals [34, 35]. Although its precise biological function is unclear, accumulating evidence indicates that α-syn plays a crucial role in regulating synaptic plasticity [36], synaptic vesicle release [37], molecular chaperoning [38], apoptosis [39], and oxidative stress [40], and it contributes to the pathogenesis of PD. α-Syn is a small 140-amino acid protein consisting of three distinct domains: the N-terminal domain (amino acids 1–65), the nonamyloid component of plaques (NAC) domain (amino acids 66–95), and the C-terminal domain (amino acids 96–140) [41,42,231], while anti-TNF therapy has been linked to a significant reduction in PD incidence and promotes the survival of dopaminergic neurons [232, 233]. Consistent with these observations, anti-TNF antibodies prevent the death of dopaminergic neurons in mice [234, 235]. The transcription factor PPARγ, expressed in neurons and glia, is a molecular link between glucose metabolism and the regulation of microglial inflammation [236]. The PPARγ agonist pioglitazone has been used in the clinic for T2DM treatment, and its effectiveness was recently evaluated in PD animal models [237]. The PPARγ agonist rosiglitazone effectively inhibits LPS-induced microglial activation, whereas the antagonist T0070907 induces a shift of microglia from an inflammatory phenotype to a homeostasis-restoring phenotype [238]. The PPARγ agonist exerts inhibitory effects on microglial activation, leading to a reduction in the production of proinflammatory factors and protecting dopaminergic neurons by modulating multiple signaling pathways, including the JUN, NK-κb, and NF-AT pathways.

The involvement of the gut microbiota in chronic inflammation and α-synuclein aggregation in the enteric nervous system presents new therapeutic opportunities that are largely unexplored. Notably, an ongoing clinical trial (NCT03958708) is investigating the effects of rifaximin, an antibiotic, in reducing systemic inflammation and α-synuclein aggregation by targeting the gut microbiota in individuals with PD. Another study (NCT03808389) is exploring the potential benefits of fecal transplantation in alleviating gut inflammation in PD patients. While most of these trials are primarily assessing clinical motor endpoints or the ability of the treatments to act on their targets, evaluating immune-related endpoints and outcomes is crucial in preclinical and clinical studies owing to the close relationship between synucleinopathies and neuroinflammation.

Conclusions, limitations, and perspectives

This review emphasizes the importance of microglia, which are located in the inflammatory environment within the CNS, in establishing a connection between neuroinflammation and α-synucleinopathies associated with PD. The exact mechanism by which disruption of microglial homeostasis contributes to α-synucleinopathy is still under investigation, but several findings suggest that microglia may act as regulators of this process. Despite the wealth of information presented in this review regarding microglia-related pathological changes, there remains significant uncertainty surrounding the specific states of microglia and their role in the pathogenesis of PD. Additionally, recent research has highlighted distinct functional variations among microglial phenotypes across different brain regions, potentially contributing to the unique patterns of microglial-mediated inflammation in PD [239]. The complexity of cellular phenotypes extends beyond conventional classifications, suggesting that further investigation is imperative for elucidating inflammation signatures associated with neurodegenerative diseases [240]. Therefore, develo** enhanced methods such as scRNA-seq or spatial transcriptomics for characterizing microglial signatures in humans or disease models would be highly advantageous to the field.

Several large-scale epidemiological and clinical studies have provided limited evidence of a relationship between intestinal diseases, gut-targeted interventions, microbiome changes, microglial homeostasis, and α-synucleinopathies [241]. Inflammation in the gut contributes to disease development through systemic mechanisms such as increased cytokine production, disruption of the blood brain barrier, migration of inflammatory cells into the brain, and activation of microglia according to studies of PD patient biopsies and fecal samples. Identifying gut microbes and metabolites that cause the disease is extremely challenging [242], as they can act independently or exert enhancing or counteracting effects within the microbial community. However, recent advances in technical and computational tools used to investigate the composition and function of the microbiome could facilitate the analysis of variations in the influence of host-associated microbial communities [243] and may provide clues for understanding the communication between the microbiome and microglia in the progression of α-synucleinopathies.

The current understanding of microglial states and their involvement in α-synucleinopathies is derived from studies utilizing diverse animal models, cell culture systems, and human samples. Researchers have made significant progress in the field by reprogramming primary microglia from fresh postmortem brains of individuals with disease or stem cells obtained from human or animal models to become microglia-like cells, enabling access to more rapid and physiological findings [244]. Recent advances in the use of human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGLs) have allowed successful recapitulation of disease phenotypes, providing a better understanding of the pathological roles of microglia in neurological diseases [245, 246]. Alternatively, the monocyte-derived microglia-like cell (MDMi) model is another in vitro culture system that  both recapitulates the genetic background of the humans from which the cells are derived [247] and allows for rapid large-scale cultivation. This system may be beneficial for exploring the interaction between the disruption of microglial homeostasis and disease progression [248, 249]. When investigating the disruption of microglial homeostasis and α-syn, model selection should be contingent on the context, with the model cells being cultured either alone or in combination with other cells, to obtain the most robust findings that reveal pertinent disease pathways. Furthermore, these findings should be cross-validated in other systems according to downstream applications to evaluate potential treatment methods.

In summary, microglia play a pivotal role in central inflammation, and the interaction of these cells with α-syn may contribute to the development of PD pathogenesis; thus, microglia are indispensable targets for therapeutic interventions.