Pathogenesis Of Parkinson's Disease Research Articles

Ultrastructural Changes of Neuroendocrine Pheochromocytoma Cell Line PC-12 Exposed In Vitro to Rotenone

Rotenone is a pesticide used in research for its ability to induce changes similar, in vivo and in vitro, to those observed in Parkinson’s disease (PD). This includes a selective death of dopaminergic neurons in the substantia nigra. Nonetheless, the precise mechanism through which rotenone modifies structure and function of neurons remains unclear. The PC12 cells closely resemble dopamine terminal neurons. This makes it a preferred model for studying the morphology of central dopamine neurons and predicting neurotoxicity. In this paper, we investigated the effects of 0.5 µM rotenone for 24–48 h on PC12 cell viability and ultrastructure (TEM), trying to identify primary and more evident alterations that can be related to neuronal damages similar to that seen in animal PD models. Cell viability decreased after 24 h rotenone treatment, with a further decrease after 48 h. Ultrastructural changes included vacuolar degeneration, mitochondrial mild swelling, decrease in the number of neuropeptide granules, and the loss of cell-to-cell adhesion. These findings are in agreement with previous research suggesting that rotenone, by inhibiting energy production and increasing ROS generation, is responsible for significant alterations of the ultrastructure and cell death of PC12 cells. Our data confirm the link between rotenone exposure, neuronal damage, and changes in dopamine metabolism, suggesting its role in the pathogenesis of PD.

A new mutation in the Parkinson's-related FBXO7 gene impairs mitochondrial and proteasomal function.

Around 10% of Parkinson's disease (PD) cases are associated with mutations in various genes, including FBXO7, which encodes the substrate-recognition component for the Skp1-Cullin-F-box (SCF) class of ubiquitin E3 ligases that target proteins for proteasomal degradation. In their recent study, Al Rawi etal. characterized a new mutation in FBXO7, L250P, in a pediatric patient. Their findings reveal that the L250P mutation abolishes Fbxo7 interaction with the proteasome regulator, proteasome inhibitor 31kD (PI31), affecting proteasomal activity and the ubiquitination of some of the ligase's targets. Furthermore, the authors show that this previously undescribed mutation impairs mitochondrial function and mitophagy, emphasizing the importance of mitochondrial and proteasomal dysfunction in PD pathogenesis.

Association Between Neuroinflammation and Parkinson's Disease: A Comprehensive Mendelian Randomization Study.

The objective of the study is to determine the causal relationship and potential mechanisms between Parkinson's disease (PD) and neuroinflammatory and neurotoxic mediators. We conducted two-sample Mendelian randomization (2SMR) study and multivariable Mendelian randomization (MVMR) analysis to investigate the causality between PD and neuroinflammatory and neurotoxic mediators. The mediation analysis with MR was also conducted to determine the potential mediating effect of neuroinflammatory and neurotoxic mediators between asthma and PD. Genetically predicted levels of nine neuroinflammation were associated with changes in PD risk. The associations of PD with CCL24, galectin-3 levels, haptoglobin, and Holo-Transcobalamin-2 remained significant in multivariable analyses. The mediation analysis with MR revealed that asthma affects PD through CCL24 and galectin-3. The results showed neuroinflammation could affect the pathogenesis of PD. In the combined analysis of these nine variables, CCL24, galectin-3 levels, HP, and Holo-Transcobalamin-2 alone were found to be significant. Asthma plays an intermediary role through CCL24 and galectin-3 levels.

The role of age-associated alpha-synuclein aggregation in a conditional transgenic mouse model of Parkinson's disease: Implications for Lewy body formation.

Parkinson's disease (PD) is a common neurodegenerative disorder that is affecting an increasing number of older adults. Although PD is mostly sporadic, genetic mutations have been found in cohorts of families with a history of familial PD (FPD). The first such mutation linked to FPD causes a point mutation (A53T) in α-synuclein (α-syn), a major component of Lewy bodies, which are a classical pathological hallmark of PD. These findings suggest that α-syn is an important contributor to the development of PD. In our previous study, we developed an adenoviral mouse model of PD and showed that the expression of wild-type (WT) α-syn or a mutant form with an increased propensity to aggregate, designated as WT-CL1 α-syn, could be used to study how α-syn aggregation contributes to PD. In this study, we established a transgenic mouse model that conditionally expresses WT or WT-CL1 α-syn in dopaminergic (DA) neurons and found that the expression of either WT or WT-CL1 α-syn was associated with an age-dependent degeneration of DA neurons and movement dysfunction. Using this model, we were able to monitor the process of α-syn aggregate formation and found a correlation between age and the number and sizes of α-syn aggregates formed. These results provide a potential mechanism by which age-dependent α-syn aggregation may lead to the formation of Lewy bodies in PD pathogenesis.

Electroacupuncture blocked motor dysfunction and gut barrier damage by modulating intestinal NLRP3 inflammasome in MPTP-induced Parkinson's disease mice

Parkinson's disease (PD) is a neurodegenerative disorder commonly accompanied by gut dysfunction. EA has shown anti-inflammatory and neuroprotective effects. Here, we aim to explore whether EA can treat Parkinson's disease by restoring the intestinal barrier and modulating NLRP3 inflammasome. We applied 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish a PD mouse model and EA at the GV16, LR3, and ST36 for 12 consecutive days. The open-field test results indicated that EA alleviated depression and behavioral defects, upregulated the expressions of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF), and blocked the accumulation of α-synuclein (α-syn) in the midbrain. Moreover, EA blocked the damage to intestinal tissues of PD mice, indicative of suppressed NLRP3 inflammasome activation and increased gut barrier integrity. Notably, the antibiotic-treated mouse experiment validated that the gut microbiota was critical in alleviating PD dyskinesia and intestinal inflammation by EA. In conclusion, this study suggested that EA exhibited a protective effect against MPTP-induced PD by alleviating behavioral defects, reversing the block of motor dysfunction, and improving the gut barrier by modulating intestinal NLRP3 inflammasome. Above all, this study could provide novel insights into the pathogenesis and therapy of PD.

Unraveling the regulatory landscape of Parkinson disease: A molecular symphony of miRNAs, transcription factors, and high-risk genes

MicroRNAs (miRNAs) have emerged as critical regulators of post-transcriptional gene expression, impacting various biological processes (development, differentiation, and progression). In medicine, miRNAs are promising diagnostic biomarkers for neurodegenerative diseases, including Parkinson's disease (PD). The current study aims at exploring the role of miRNAs and transcription factors (TFs) in regulating genes-associated with PD. Deploying bioinformatics tools, the study identifies specific miRNAs and TFs involved in PD and their potential connections to the organ-disease junction. Notably, certain miRNAs are found to be highly expressed in brain, than compared to blood. Furthermore, the study explores the expression patterns of PD-related genes in different regions of the brain and attempts to construct complex network of interactions contributing to PD pathogenesis. Additionally, the regulatory relationship of two miRNAs namely hsa-miR-375-3p and hsa-miR-423-3p with TFs are well examined. Overall, the study provides a comprehensive moon-shot view of the molecular aspects of PD and their potential therapeutic targets which could be further used as diagnostic biomarkers in early detection, drug design and development attributing towards precision medicine.

Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics

: Despite the extensive research successes and continuous developments in modern medicine in terms of diagnosis, prevention, and treatment, the lack of clinically useful disease-modifying drugs or immunotherapeutic agents that can successfully treat or prevent neurodegenerative diseases is an ongoing challenge. To date, only one of the 244 drugs in clinical trials for the treatment of neurodegenerative diseases has been approved in the past decade, indicating a failure rate of 99.6%. In corollary, the approved monoclonal antibody did not demonstrate significant cognitive benefits. Thus, the prevalence of neurodegenerative diseases is increasing rapidly. Therefore, there is an urgent need for creative approaches to identifying and testing biomarkers for better diagnosis, prevention, and disease-modifying strategies for the treatment of neurodegenerative diseases. Overexpression of the endogenous α-synuclein has been identified as the driving force for the formation of the pathogenic α-synuclein (α-Syn) conformers, resulting in neuroinflammation, hypersensitivity, endogenous homeostatic responses, oxidative dysfunction, and degeneration of dopaminergic neurons in Parkinson’s disease (PD). However, the conformational plasticity of α-Syn proffers that a certain level of α-Syn is essential for the survival of neurons. Thus, it exerts both neuroprotective and neurotoxic (regulatory) functions on neighboring neuronal cells. Furthermore, the aberrant metastable α-Syn conformers may be subtle and difficult to detect but may trigger cellular and molecular events including immune responses. It is well documented in literature that the misfolded α-Syn and its conformers that are released into the extracellular space from damaged or dead neurons trigger the innate and adaptive immune responses in PD. Thus, in this review, we discuss the nonintuitive plasticity and immunogenicity of the α-Syn conformers in the brain immune cells and their physiological and pathological consequences on the neuroimmune responses including neuroinflammation, homeostatic remodeling, and cell-specific interactions that promote neuroprotection in PD. We also critically reviewed the novel strategies for immunotherapeutic delivery interventions in PD pathogenesis including immunotherapeutic targets and potential nanoparticle-based smart drug delivery systems. It is envisioned that a greater understanding of the nonintuitive immunogenicity of aberrant α-Syn conformers in the brain’s microenvironment would provide a platform for identifying valid therapeutic targets and developing smart brain delivery systems for clinically effective disease-modifying immunotherapeutics that can aid in the prevention and treatment of PD in the future.

Interplay between α-synuclein and parkin genes: Insights of Parkinson's disease.

Parkinson's disease (PD) is a complex and debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The pathogenesis of PD is intimately linked to the roles of two key molecular players, α-synuclein (α-syn) and Parkin. Understanding the intricate interplay between α-syn and Parkin is essential for unravelling the molecular underpinnings of PD. Their roles in synaptic function and protein quality control underscore their significance in neuronal health. Dysregulation of these processes, as seen in PD, highlights the potential for targeted therapeutic strategies aimed at restoring normal protein homeostasis and mitigating neurodegeneration. Investigating the connections between α-syn, Parkin, and various pathological mechanisms provides insights into the complex web of factors contributing to PD pathogenesis and offers hope for the development of more effective treatments for this devastating neurological disorder. The present compilation provides an overview of their structures, regional and cellular locations, associations, physiological functions, and pathological roles in the context of PD.

Interplay of human gastrointestinal microbiota metabolites: Short-chain fatty acids and their correlation with Parkinson's disease.

Short-chain fatty acids (SCFAs) are, the metabolic byproducts of intestinal microbiota that, are generated through anaerobic fermentation of undigested dietary fibers. SCFAs play a pivotal role in numerous physiological functions within the human body, including maintaining intestinal mucosal health, modulating immune functions, and regulating energy metabolism. In recent years, extensive research evidence has indicated that SCFAs are significantly involved in the onset and progression of Parkinson disease (PD). However, the precise mechanisms remain elusive. This review comprehensively summarizes the progress in understanding how SCFAs impact PD pathogenesis and the underlying mechanisms. Primarily, we delve into the synthesis, metabolism, and signal transduction of SCFAs within the human body. Subsequently, an analysis of SCFA levels in patients with PD is presented. Furthermore, we expound upon the mechanisms through which SCFAs induce inflammatory responses, oxidative stress, abnormal aggregation of alpha-synuclein, and the intricacies of the gut-brain axis. Finally, we provide a critical analysis and explore the potential therapeutic role of SCFAs as promising targets for treating PD.

Protective effect of increased O-GlcNAc cycling against 6-OHDA induced Parkinson’s disease pathology

This study aimed to elucidate the role of O-GlcNAc cycling in 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD)-like neurodegeneration and the underlying mechanisms. We observed dose-dependent downregulation of O-GlcNAcylation, accompanied by an increase in O-GlcNAcase following 6-OHDA treatment in both mouse brain and Neuro2a cells. Interestingly, elevating O-GlcNAcylation through glucosamine (GlcN) injection provided protection against PD pathogenesis induced by 6-OHDA. At the behavioral level, GlcN mitigated motor deficits induced by 6-OHDA, as determined using the pole, cylinder, and apomorphine rotation tests. Furthermore, GlcN attenuated 6-OHDA-induced neuroinflammation and mitochondrial dysfunction. Notably, augmented O-GlcNAcylation, achieved through O-GlcNAc transferase (OGT) overexpression in mouse brain, conferred protection against 6-OHDA-induced PD pathology, encompassing neuronal cell death, motor deficits, neuroinflammation, and mitochondrial dysfunction. These collective findings suggest that O-GlcNAcylation plays a crucial role in the normal functioning of dopamine neurons. Moreover, enhancing O-GlcNAcylation through genetic and pharmacological means could effectively ameliorate neurodegeneration and motor impairment in an animal model of PD. These results propose a potential strategy for safeguarding against the deterioration of dopamine neurons implicated in PD pathogenesis.

The Role of Oxygen Homeostasis and the HIF-1 Factor in the Development of Neurodegeneration.

Understanding the molecular underpinnings of neurodegeneration processes is a pressing challenge for medicine and neurobiology. Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent forms of neurodegeneration. To date, a substantial body of experimental evidence has strongly implicated hypoxia in the pathogenesis of numerous neurological disorders, including AD, PD, and other age-related neurodegenerative conditions. Hypoxia-inducible factor (HIF) is a transcription factor that triggers a cell survival program in conditions of oxygen deprivation. The involvement of HIF-1α in neurodegenerative processes presents a complex and sometimes contradictory picture. This review aims to elucidate the current understanding of the interplay between hypoxia and the development of AD and PD, assess the involvement of HIF-1 in their pathogenesis, and summarize promising therapeutic approaches centered on modulating the activity of the HIF-1 complex.

Epidemiology of Parkinson's Disease: An Update.

In recent decades, epidemiological understanding of Parkinson disease (PD) has evolved significantly. Major discoveries in genetics and large epidemiological investigations have provided a better understanding of the genetic, behavioral, and environmental factors that play a role in the pathogenesis and progression of PD. In this review, we provide an epidemiological update of PD with a particular focus on advances in the last five years of published literature. We include an overview of PD pathophysiology, followed by a detailed discussion of the known distribution of disease and varied determinants of disease. We describe investigations of risk factors for PD, and provide a critical summary of current knowledge, knowledge gaps, and both clinical and research implications. We emphasize the need to characterize the epidemiology of the disease in diverse populations. Despite increasing understanding of PD epidemiology, recent paradigm shifts in the conceptualization of PD as a biological entity will also impact epidemiological research moving forward and guide further work in this field.

A crazy trio in Parkinson's disease: metabolism alteration, α-synuclein aggregation, and oxidative stress.

Parkinson's disease (PD) is an aging-associated neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies containing α-synuclein within these neurons. Oligomeric α-synuclein exerts neurotoxic effects through mitochondrial dysfunction, glial cell inflammatory response, lysosomal dysfunction and so on. α-synuclein aggregation, often accompanied by oxidative stress, is generally considered to be a key factor in PD pathology. At present, emerging evidences suggest that metabolism alteration is closely associated with α-synuclein aggregation and PD progression, and improvement of key molecules in metabolism might be potentially beneficial in PD treatment. In this review, we highlight the tripartite relationship among metabolic changes, α-synuclein aggregation, and oxidative stress in PD, and offer updated insights into the treatments of PD, aiming to deepen our understanding of PD pathogenesis and explore new therapeutic strategies for the disease.

The role of the brain renin-angiotensin system in Parkinson´s disease.

The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood-brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.

Experimental Models to Study Immune Dysfunction in the Pathogenesis of Parkinson's Disease.

Parkinson's disease (PD) is a chronic, age-related, progressive multisystem disease associated with neuroinflammation and immune dysfunction. This review discusses the methodological approaches used to study the changes in central and peripheral immunity in PD, the advantages and limitations of the techniques, and their applicability to humans. Although a single animal model cannot replicate all pathological features of the human disease, neuroinflammation is present in most animal models of PD and plays a critical role in understanding the involvement of the immune system (IS) in the pathogenesis of PD. The IS and its interactions with different cell types in the central nervous system (CNS) play an important role in the pathogenesis of PD. Even though culture models do not fully reflect the complexity of disease progression, they are limited in their ability to mimic long-term effects and need validation through in vivo studies. They are an indispensable tool for understanding the interplay between the IS and the pathogenesis of this disease. Understanding the immune-mediated mechanisms may lead to potential therapeutic targets for the treatment of PD. We believe that the development of methodological guidelines for experiments with animal models and PD patients is crucial to ensure the validity and consistency of the results.

Current trends in basic research on Parkinson's disease: from mitochondria, lysosome to α-synuclein.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and other brain regions. A key pathological feature of PD is the abnormal accumulation of α-synuclein protein within affected neurons, manifesting as Lewy bodies and Lewy neurites. Despite extensive research efforts spanning several decades, the underlying mechanisms of PD and disease-modifying therapies remain elusive. This review provides an overview of current trends in basic research on PD. Initially, it discusses the involvement of mitochondrial dysfunction in the pathogenesis of PD, followed by insights into the role of lysosomal dysfunction and disruptions in the vesicular transport system. Additionally, it delves into the pathological and physiological roles of α-synuclein, a crucial protein associated with PD pathophysiology. Overall, the purpose of this review is to comprehend the current state of elucidating the intricate mechanisms underlying PD and to outline future directions in understanding this disease.

Plasminogen degrades α-synuclein, Tau and TDP-43 and decreases dopaminergic neurodegeneration in mouse models of Parkinson’s disease

Parkinson's disease (PD) is the second most frequently diagnosed neurodegenerative disease, and it is characterized by the intracellular and extracellular accumulation of α-synuclein (α-syn) and Tau, which are major components of cytosolic protein inclusions called Lewy bodies, in the brain. Currently, there is a lack of effective methods that preventing PD progression. It has been suggested that the plasminogen activation system, which is a major extracellular proteolysis system, is involved in PD pathogenesis. We investigated the functional roles of plasminogen in vitro in an okadaic acid-induced Tau hyperphosphorylation NSC34 cell model, ex vivo using brains from normal controls and methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, and in vivo in a widely used MPTP-induced PD mouse model and an α-syn overexpression mouse model. The in vitro, ex vivo and in vivo results showed that the administered plasminogen crossed the blood‒brain barrier (BBB), entered cells, and migrated to the nucleus, increased plasmin activity intracellularly, bound to α-syn through lysine binding sites, significantly promoted α-syn, Tau and TDP-43 clearance intracellularly and even intranuclearly in the brain, decreased dopaminergic neurodegeneration and increased the tyrosine hydroxylase levels in the substantia nigra and striatum, and improved motor function in PD mouse models. These findings indicate that plasminogen plays a wide range of pivotal protective roles in PD and therefore may be a promising drug candidate for PD treatment.

MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX

ABSTRACT Mutations in the PINK1 kinase cause Parkinson disease (PD) through physiological processes that are not yet fully elucidated. PINK1 kinase accumulates selectively on damaged mitochondria, where it recruits the E3 ubiquitin ligase PRKN/Parkin to mediate mitophagy. Upon mitochondrial import failure, PINK1 accumulates in association with the translocase of outer mitochondrial membrane (TOMM). However, the molecular basis of this PINK1 accumulation on the TOMM complex remain elusive. We recently demonstrated that TIMM23 (translocase of the inner mitochondrial membrane 23) is a component of the PINK1-supercomplex formed in response to mitochondrial stress. We also uncovered that PINK1 is required for the formation of this supercomplex and highlighted the biochemical regulation and significance of this supercomplex; expanding our understanding of mitochondrial quality control and PD pathogenesis.

The Interaction Between Nutraceuticals and Gut Microbiota: a Novel Therapeutic Approach to Prevent and Treatment Parkinson's Disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons, leading to motor and non-motor symptoms. Emerging research has shed light on the role of gut microbiota in the pathogenesis and progression of PD. Nutraceuticals such as curcumin, berberine, phytoestrogens, polyphenols (e.g., resveratrol, EGCG, and fisetin), dietary fibers have been shown to influence gut microbiota composition and function, restoring microbial balance and enhancing the gut-brain axis. The mechanisms underlying these benefits involve microbial metabolite production, restoration of gut barrier integrity, and modulation of neuroinflammatory pathways. Additionally, probiotics and prebiotics have shown potential in promoting gut health, influencing the gut microbiome, and alleviating PD symptoms. They can enhance the gut's antioxidant capacity of the gut, reduce inflammation, and maintain immune homeostasis, contributing to a neuroprotective environment. This paper provides an overview of the current state of knowledge regarding the potential of nutraceuticals and gut microbiota modulation in the prevention and management of Parkinson's disease, emphasizing the need for further research and clinical trials to validate their effectiveness and safety. The findings suggest that a multifaceted approach involving nutraceuticals and gut microbiota may open new avenues for addressing the challenges of PD and improving the quality of life for affected individuals.

Single cell analysis reveals the roles and regulatory mechanisms of type-I interferons in Parkinson’s disease

The pathogenesis of Parkinson’s disease (PD) is strongly associated with neuroinflammation, and type I interferons (IFN-I) play a crucial role in regulating immune and inflammatory responses. However, the specific features of IFN in different cell types and the underlying mechanisms of PD have yet to be fully described. In this study, we analyzed the GSE157783 dataset, which includes 39,024 single-cell RNA sequencing results for five PD patients and six healthy controls from the Gene Expression Omnibus database. After cell type annotation, we intersected differentially expressed genes in each cell subcluster with genes collected in The Interferome database to generate an IFN-I-stimulated gene set (ISGs). Based on this gene set, we used the R package AUCell to score each cell, representing the IFN-I activity. Additionally, we performed monocle trajectory analysis, and single-cell regulatory network inference and clustering (SCENIC) to uncover the underlying mechanisms. In silico gene perturbation and subsequent experiments confirm NFATc2 regulation of type I interferon response and neuroinflammation. Our analysis revealed that microglia, endothelial cells, and pericytes exhibited the highest activity of IFN-I. Furthermore, single-cell trajectory detection demonstrated that microglia in the midbrain of PD patients were in a pro-inflammatory activation state, which was validated in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model as well. We identified transcription factors NFATc2, which was significantly up-regulated and involved in the expression of ISGs and activation of microglia in PD. In the 1-Methyl-4-phenylpyridinium (MPP+)-induced BV2 cell model, the suppression of NFATc2 resulted in a reduction in IFN-β levels, impeding the phosphorylation of STAT1, and attenuating the activation of the NF-κB pathway. Furthermore, the downregulation of NFATc2 mitigated the detrimental effects on SH-SY5Y cells co-cultured in conditioned medium. Our study highlights the critical role of microglia in type I interferon responses in PD. Additionally, we identified transcription factors NFATc2 as key regulators of aberrant type I interferon responses and microglial pro-inflammatory activation in PD. These findings provide new insights into the pathogenesis of PD and may have implications for the development of novel therapeutic strategies.