GRAPHICAL ABSTRACT

INTRODUCTION

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons and the pathological accumulation of α-synuclein in the form of Lewy bodies—a hallmark of synucleinopathy. Accumulating evidence suggests that neuroinflammation, involving both central and peripheral immune responses, plays a pivotal role in the pathogenesis and progression of PD [1]. Among the various inflammatory pathways, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has emerged as a critical downstream effector contributing to PD-related neurodegeneration.

The NLRP3 inflammasome is a multiprotein complex composed of the NLRP3 sensor, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and the effector protease caspase-1 [2]. Upon activation, this complex facilitates the cleavage of pro-caspase-1 into its active form, which in turn transforms proinflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18) into their mature, bioactive forms [3]. Additionally, NIMA-related kinase 7 (NEK7) has been identified as an essential regulatory component in the assembly of the NLRP3 inflammasome complex, acting as a scaffold that facilitates NLRP3 oligomerization and activation in response to various cellular stress signals, such as pathological α-synuclein [4,5].

Multiple studies have demonstrated elevated expression and activation of NLRP3 inflammasome components in both postmortem brain tissues and peripheral blood mononuclear cells (PBMCs) from patients with PD, suggesting that peripheral immune system involvement may mirror or even contribute to central neuroinflammatory processes [6-9]. However, other reports have presented conflicting findings, indicating variability in NLRP3 activity based on disease stage or heterogeneity across patient subgroups [10]. These discrepancies underscore the need for a more nuanced understanding of the temporal and pathological dynamics of NLRP3 activation across the spectrum of synucleinopathies.

This study aimed to elucidate the expression profiles of NLRP3 inflammasome-related genes—NLRP3, ASC, caspase-1, and NEK7—and their downstream cytokines IL-1β and IL-18 in PBMCs. We specifically investigated their differential expression across patients with various stages of PD, including the prodromal phase, which is characterized by idiopathic REM sleep behavior disorder (iRBD), as well as multiple system atrophy (MSA), a clinically and pathologically distinct synucleinopathy. By exploring peripheral inflammasome activity in these groups, we sought to clarify the role of immune-related pathways in disease progression and the potential for biomarker-based differentiation between PD and related disorders. Previous discrepancies in inflammasome activity reported by different studies may arise from differences in patient characteristics, stages of disease progression, medication effects, or analytical methodologies, emphasizing the need for systematic analyses across multiple disease stages.

MATERIALS & METHODS

Participants

Participants were recruited from Hallym University Sacred Heart Hospital and Seoul National University Hospital between February 2021 and January 2024. A total of 35 healthy controls (HCs), 31 individuals with iRBD, 41 with early-stage PD, 21 with late-stage PD, and 23 with MSA were included.

The diagnosis of PD was based on the Movement Disorder Society (MDS) Clinical Diagnostic Criteria for Parkinson’s Disease [11]. Patients classified as having early-stage PD were drugnaïve and had symptom onset within the previous three years, whereas those in the late-stage PD group had a duration of disease of five years or more after diagnosis. All PD diagnoses were made based on the MDS criteria and supported by dopaminergic deficit findings on 18F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography (PET) imaging.

Participants in the iRBD group, who were considered to have a prodromal stage of synucleinopathy, exhibited no clinical signs of parkinsonism and had a diagnosis of idiopathic RBD confirmed via overnight polysomnography. The diagnosis of MSA was based on the MDS Diagnostic Criteria for Multiple System Atrophy revised in 2022 [12]. Patients with cerebrovascular disease, other neurodegenerative diseases, or systemic inflammatory diseases were excluded. Patients with current infections at the time of enrollment were also excluded from the study.

Data collection included demographic information procurement, detailed clinical evaluations, and biospecimen sampling. Clinical assessments were conducted using the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Unified Multiple System Atrophy Rating Scale (UMSARS), and Hoehn and Yahr staging system. Blood samples were drawn after written informed consent was obtained from all participants, and no adverse events related to sample collection were reported.

On the day of enrollment, participants with PD and those with iRBD underwent MDS-UPDRS assessment, while participants with MSA were assessed using the UMSARS. In the early-stage PD group, MDS-UPDRS assessments were conducted in the drug-naïve state, whereas in the late-stage PD group, evaluations were performed while patients were receiving antiparkinsonian medications (On status). The Korean version of the Montreal Cognitive Assessment (K-MoCA) was additionally performed in patients with early-stage PD. A 10 mL peripheral blood sample was obtained from each subject using heparinized collection tubes and stored under appropriate conditions for subsequent analysis.

Ethical statement

This study was approved by the institutional review board of Hallym University Medical Center (IRB 2020-06-106). Informed consent was obtained from all participants, and all evaluations were conducted in accordance with the ethical standards of the institutional committee, as well as the 1964 Helsinki Declaration and its later amendments.

PBMC isolation

Blood samples stored in heparin tubes were immediately processed using Ficoll–Paque PLUS (GE Healthcare) for density-gradient centrifugation. The blood was diluted 1:2 with phosphate-buffered saline and gently layered onto Ficoll. After centrifugation, the PBMC layer was collected into microcentrifuge tubes and stored at -80°C.

RNA extraction from PBMCs

Total RNA was extracted using TRIzol reagent (Invitrogen, Thermo Fisher Scientific) following the manufacturer’s protocol. Briefly, TRIzol was added to the cell pellet in proportion to the number of PBMCs, and the samples were thoroughly homogenized. Phase separation was achieved by the addition of chloroform, after which the RNA was precipitated with isopropanol. The RNA pellet was subsequently washed three times with ethanol and then dissolved in 20 μL of RNase-free water. RNA concentration and purity were assessed using a Nano-Drop spectrophotometer. For subsequent quantitative polymerase chain reaction (qPCR) analysis, 200 ng of RNA was reverse transcribed into complementary DNA (cDNA) using the RevertAid First Strand cDNA Synthesis Kit (Thermo Fisher Scientific).

Real-time polymerase chain reaction

mRNA expression levels of four components of the NLRP3 inflammasome (NLRP3, ASC, caspase-1, and NEK7) and two cytokines (IL-1β and IL-18) were assessed. SYBR Green qPCR assays were performed using Power SYBR Green Master Mix (Life Technologies). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as the internal control for relative quantification. The expression levels were calculated using the comparative Ct (2^–ΔΔCt) method.

The sequences of the primers used for qPCR are listed in Supplementary Table 1. All the qPCRs were performed in duplicate under the following cycling conditions: The holding stage was set at 95°C for 10 minutes to activate the hot-start DNA polymerase. The cycling stage was subsequently conducted with denaturation at 95°C for 15 seconds and annealing/extension at 60°C for 60 seconds, which was repeated for 45 cycles. After amplification, melting curve analysis was performed: the samples were first heated to 95°C for 15 seconds and then cooled to 60°C for 1 minute to allow reannealing, after which the temperature was gradually increased from 60°C to 95°C at a rate of 0.3°C per second while fluorescence signals were continuously recorded.

Statistical analysis

For continuous variables, comparisons between two groups were performed using either Student’s t-test or the Mann–Whitney U test, depending on the data distribution. For comparisons among more than two groups, one-way analysis of variance (ANOVA) or Welch’s ANOVA was applied. To correct for multiple comparisons, a Bonferroni correction was performed. For categorical variables, group comparisons were conducted using the chi-square test. In the early-stage PD group, associations between mRNA expression levels and clinical variables were assessed using stepwise multiple linear regression analysis with mixed selection. The independent variables included age; sex; disease duration; modified Hoehn and Yahr (H&Y) stage; and MDS-UPDRS Part I, II, and III and K-MoCA scores. In stepwise multiple linear regression analyses, variables were entered at a significance level of p<0.05 and removed at p>0.10.

RESULTS

A total of 35 HCs, 31 participants with iRBD, 41 patients with early-stage PD, 21 patients with late-stage PD, and 23 patients with MSA were included in this study. The clinical characteristics of the participants are summarized in Table 1. Age at evaluation was oldest in the late-stage PD group, and patients with MSA were youngest among the groups. The disease duration was 1.07±0.99 years in the early-stage PD group, 9.89±3.72 years in the late-stage PD group, and 3.74±3.12 years in the MSA group. As expected, the UPDRS score increased progressively across the groups, from iRBD to early-stage PD and then to late-stage PD.

The mRNA expression levels of NLRP3 inflammasome components and related cytokines across disease groups are shown in Figure 1. NLRP3 expression was significantly lower in both the iRBD and early-stage PD groups than in the HC group (p=0.0263 and p=0.0101, respectively) (Figure 1A). NEK7 expression progressively decreased across the disease spectrum and was lower in patients with iRBD, those with early-stage PD, and those with late-stage PD than in healthy controls. Compared with the controls, both the early-stage PD group and the late-stage PD group exhibited significantly reduced NEK7 expression (p=0.0008 and p<0.0001). Moreover, compared with those in the iRBD group, NEK7 levels in early- and late-stage PD groups were significantly lower (p=0.0111 and p=0.0001, respectively). In contrast, NEK7 expression in the MSA group was comparable to that in the HCs and was significantly higher than that in the PD group (HC vs. MSA, p>0.9999; early- and late-stage PD vs. MSA, p=0.0006 and p<0.0001, respectively) (Figure 1B).

The expression of the adaptor protein ASC, which is shared among multiple inflammasome pathways, exhibited a pattern opposite to that of NLRP3 and NEK7. It was elevated in patients across the PD spectrum compared with that in HCs, with significantly higher levels observed in both the early- and late-stage PD groups (p=0.0157 and p=0.0007, respectively). Additionally, ASC expression was significantly greater in the early-and late-stage PD groups than in the iRBD group (p=0.0213 and p=0.0009, respectively). In contrast, ASC levels in the MSA group were comparable to those in the HCs group and were significantly lower than those in the early- and late-stage PD groups (p=0.0005 and p<0.0001) (Figure 1C).

The expression of the effector protease caspase-1, which functions downstream of multiple inflammasome pathways, showed a groupwise expression pattern similar to that of ASC expression. Caspase-1 levels were significantly greater in the late-stage PD group than in the HC group and were greater in the late-stage PD group than in the iRBD group (p=0.0221 and p<0.0001). In the MSA group, caspase-1 expression was comparable to that in the HC group and significantly lower than that in the late-stage PD group (p>0.9999 and p=0.0101, respectively) (Figure 1D). IL-1β and IL-18, the key downstream products of the NLRP3 inflammasome pathway, did not significantly differ or clearly trend across the groups (Figure 1E and F).

Table 2 presents the results of multiple linear regression analysis assessing clinical variables associated with NLRP3 mRNA expression in patients with early-stage PD. The optimal model indicated that NLRP3 mRNA expression was negatively correlated with disease duration, the MDS-UPDRS Part II score, and the K-MoCA score. This finding is consistent with the observed reduction in NLRP3 expression from that in HCs to that in individuals with iRBD to that in patients with early-stage PD, as shown in Figure 1. Caspase-1 expression was also negatively correlated with MDS-UPDRS scores. No significant clinical variables were associated with NEK7 or ASC expression levels. The results of multiple linear regression analysis for the total PD group (early- and late-stage PD groups) are presented in Supplementary Table 2. NLRP3 expression was negatively associated with the modified H&Y stage. However, this analysis included only five additional patients from the late-stage PD group because of the limited availability of K-MoCA data.

DISCUSSION

In this study, we examined the mRNA expression profiles of NLRP3 inflammasome-related genes (NLRP3, NEK7, ASC, and caspase-1) and associated cytokines (IL-1β and IL-18) in PBMCs in patients across different stages of PD, including iRBD, early-stage PD, late-stage PD, and MSA. We observed a progressive decrease in NLRP3 and NEK7 expression levels from the prodromal stage (iRBD) through early- to late-stage PD. Conversely, the expression of ASC and caspase-1 was elevated in patients in later stages of PD, suggesting the potential involvement of alternative inflammasome pathways independent of NLRP3. Notably, the inflammasome expression levels of patients with MSA were comparable to those of healthy controls, emphasizing the distinction between peripheral and central inflammatory processes.

In contrast to several earlier studies reporting NLRP3 inflammasome activation in PD patients, we observed a progressive decrease in NLRP3 and NEK7 mRNA expression from iRBD through early-stage PD to late-stage PD. Solini et al. [9] reported elevated NLRP3 and caspase-1 expression in PBMCs from treatment-naïve patients with early-stage PD, which decreased after dopaminergic treatment. Although this has been interpreted as a treatment effect, it is also possible that the observed reduction reflects a natural decline in inflammasome activation associated with disease progression itself, as supported by our finding of progressive downregulation from individuals with iRBD to those with late-stage PD. Notably, when patients with iRBD and those with early-stage PD were compared, a trend toward decreased NLRP3 and NEK7 mRNA expression was observed even in the absence of levodopa treatment. In a previous study using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, levodopa treatment suppressed NLRP3 expression [13]. However, the MPTP-induced PD mouse model does not sufficiently reflect α-synuclein pathology, and its inflammatory responses may differ from those observed during the actual progression of PD.

Notably, the literature has long been inconsistent regarding NLRP3 activation in patients with PD. While some studies have shown elevated inflammasome activity in brain tissue and blood [6-9], others, such as the large-scale genetic study by Senkevich et al. [10], have reported no significant associations between NLRP3 gene variants and PD risk or progression. Some studies have suggested that NLRP3 activation does not consistently lead to downstream inflammatory cytokine release under certain experimental conditions [14], suggesting that the link between NLRP3 activation and PD progression may not be straightforward. This ambiguity highlights the importance of examining inflammasome behavior across different stages of the disease to determine whether its activity naturally diminishes with progression.

In this context, our study provides important contributions by capturing expression profiles across a disease continuum—from prodromal (iRBD) to late-stage PD—in a treatment-diverse population, using PBMCs as a minimally invasive yet immune-relevant peripheral tissue source. Unlike some previous studies that focused solely on a single disease stage or treatment-naïve cohort, our stratified design allows for the identification of stage-specific trends, such as the progressive downregulation of NLRP3 and NEK7 expression. This longitudinal perspective may help address some of the discrepancies in the literature and highlights the potential of PBMC profiling as a dynamic biomarker platform in neurodegenerative disease research. Furthermore, the consistency between NLRP3 and NEK7—an essential and specific adaptor for NLRP3 inflammasome activation—adds credibility to our findings, as NEK7 has been shown to be an NLRP3-specific adaptor protein that is required for NLRP3 inflammasome activation [4].

Interestingly, we observed elevated ASC and caspase-1 expression in patients in the later stages of PD. Given that both proteins are also shared components of multiple canonical inflammasomes, such as absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4)—not limited to NLRP3—their upregulation may indicate the activation of other inflammasome pathways independent of NLRP3 [15,16]. The negative correlation between caspase-1 expression and MDS-UPDRS Part II scores in the multiple linear regression analysis may similarly reflect this dynamic. Although not statistically definitive, the reduced caspase-1 expression in individuals with iRBD, followed by a progressive increase with disease progression, further suggests the involvement of inflammasome pathways beyond NLRP3.

In patients with MSA, our data revealed no significant upregulation of inflammasome components in PBMCs, in contrast to the findings of Li et al. [17], who reported increased expression of NLRP3-related proteins in the putamen of postmortem brains of patients with MSA. This discrepancy may reflect several factors, including the contrast between central and peripheral immune responses, differences in the biological material analyzed (postmortem brain tissue vs. PBMCs), and variability in patient cohorts such as age, disease stage, or treatment status. While our study included MSA as a disease control group to compare systemic immune profiles across synucleinopathies, it is important to recognize that the underlying pathophysiology of MSA—driven primarily by oligodendroglial inclusions and regional glial activation—differs substantially from that of PD. Thus, although MSA inclusion offers insights into disease-specific inflammatory profiles, assessments of mechanisms directly relevant to PD progression may be limited. Given that MSA pathology predominantly involves central nervous system (CNS)-specific glial activation and oligodendroglial inclusions, peripheral blood may not adequately reflect central inflammasome changes. Therefore, our findings do not exclude the possibility of central NLRP3 inflammasome involvement in MSA pathology. Nevertheless, even if peripheral inflammasome signatures do not fully reflect CNS pathology in MSA, evaluating them remains meaningful in the search for accessible, noninvasive biomarkers that can differentiate synucleinopathies and capture systemic immune alterations that may accompany disease progression.

Recent theories on PD pathology have increasingly emphasized bidirectional progression models, such as “brain-first” and “body-first” mechanisms. Peripheral inflammation, which has been extensively documented in PD through various studies, has been shown to directly or indirectly influence CNS progression in animal models [18,19]. Thus, inflammation is now widely accepted as a crucial contributing factor to PD pathogenesis. Nevertheless, the specific inflammatory pathways involved remain incompletely understood. In this context, the role of inflammasomes as significant intracellular mediators of inflammatory responses warrants further exploration.

Our study has several limitations. First, we analyzed peripheral blood samples, which may not fully capture central pathological changes, which are especially relevant in disorders such as MSA characterized by predominant central pathology. Nevertheless, importantly, the primary goal of utilizing peripheral blood samples was specifically to investigate peripheral immune changes rather than central pathological changes. Peripheral changes are increasingly recognized as critical contributors to PD pathogenesis, supporting the rationale for focusing on peripheral immune responses. Second, mRNA expression levels do not necessarily correspond directly to protein functionality, necessitating further investigation into protein-level inflammasome activity. For instance, the lack of significant changes in IL-1β and IL-18 expression could reflect regulatory mechanisms at the posttranscriptional or translational level, limiting direct inference of inflammasome activity solely from mRNA expression data. Nevertheless, mRNA expression reflects the priming state of the inflammasome pathway, capturing stage-dependent alterations in peripheral immune signatures across synucleinopathies. Third, data concerning comorbid conditions such as diabetes, obesity, and cardiovascular disease were not systematically collected or adjusted for, despite their potential influence on peripheral inflammation. No concomitant medications were used. Fourth, we did not stratify patients according to clinical subtypes (e.g., tremor-dominant versus postural instability and gait difficulty in PD or MSA-P versus MSA-C), which may exhibit different inflammatory signatures. Finally, genetic studies, including genome-wide association studies (GWASs) and monogenic PD analyses, have not identified NLRP3, NEK7 or ASC as risk loci, which limits genetic support for their causal involvement. These limitations mean that our findings should be interpreted as observational and hypothesis generating. Further clarification of the role of inflammasome pathways in PD and related synucleinopathies will require longitudinal studies tracking individual patients over time, combined with protein-level, clinical, and genetic validation.

Taken together, our findings suggest that canonical NLRP3 inflammasome activation in the periphery may not play a consistent or central role in PD progression. Instead, peripheral expression may fluctuate with disease stage or treatment status or reflect compensatory immune changes rather than direct pathology. The increased ASC and caspase-1 levels, however, indicate that other inflammasome pathways or immune axes could still be active and deserve further investigation.

In conclusion, our analysis revealed a progressive decrease in NLRP3 and NEK7 expression in PBMCs from patients with iRBD to those with late-stage PD, challenging prior findings of inflammasome activation in PD and aligning with recent genetic data questioning the causal role of NLRP3. However, ASC and caspase-1 expression patterns suggest residual or alternative inflammasome activity. No peripheral inflammasome activation was observed in patients with MSA, suggesting that inflammatory mechanisms underlying MSA are distinct from those underlying PD. These findings highlight the nuanced and stage-dependent nature of immune responses in neurodegenerative diseases and caution against generalized therapeutic targeting of NLRP3 without consideration of patient stratification and disease phase.

Supplementary Materials

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This research was supported by a grant of the Korea Health Technology R&D Project through the Korean Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2023-00265159). Basic Science Research Program through the National Research Foundation of Korea (NRF) grant funded by the Ministry of education (RS-2023-00246655), the National Research Foundation of Korea (NRF) by the Korea government (MSIT) (2022R1A2C2091254), Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (RS-2023-00223501).

Acknowledgments

None

Author Contributions

Conceptualization: Jeongjae Lee, Young Eun Kim. Data curation: Jeongjae Lee, Han-Joon Kim, In Hee Kwak, Hyeo-il Ma, Young Eun Kim. Formal analysis: Jeongjae Lee, Young Eun Kim. Funding acquisition: Young Eun Kim. Investigation: Jeongjae Lee, Hye Joung Choi, Huu Dat Nguyen, Suk Jun Song, Trung Nguyen Thanh. Methodology: Jeongjae Lee, Young Eun Kim, Hye Joung Choi. Project administration: Young Eun Kim, Jeongjae Lee. Resources: Jeongjae Lee, Han-Joon Kim, In Hee Kwak, Hyeo-il Ma, Young Eun Kim. Software: Jeongjae Lee. Supervision: Young Eun Kim, Hyeo-il Ma. Validation: Jeongjae Lee, Young Eun Kim. Visualization: Jeongjae Lee. Writing—original draft: Jeongjae Lee. Writing—review & editing: all authors.

Figure 1.

Relative mRNA expression of NLRP3 inflammasome components and cytokines across disease groups. A: NLRP3. B: NEK7. C: ASC. D: Caspase-1. E: IL-1β. F: IL-18. *p<0.05; **p<0.01; ***p<0.001. NLRP3, NOD-like receptor family pyrin domain-containing 3; NEK7, NIMA-related kinase 7; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; HCs, healthy controls; iRBD, isolated REM sleep behavior disorder; PD, Parkinson’s disease; MSA, multiple system atrophy; IL-1β, interleukin-1 beta; IL-18, interleukin 18.

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