Parkinson's disease has long been considered a disorder that primarily affects the brain, as it is defined by the dopaminergic neurodegeneration in the substantia nigra and the brain accumulation of Lewy bodies containing α-synuclein protein. In recent decades, however, accumulating research has revealed that Parkinson's disease also involves the gut and uncovered an intimate and important bidirectional link between the brain and the gut, called the "gut-brain axis." Numerous clinical studies demonstrate that gut dysfunction frequently precedes motor symptoms in Parkinson's disease patients, with findings including impaired intestinal permeability, heightened inflammation, and distinct gut microbiome profiles and metabolites. Furthermore, α-synuclein deposition has been consistently observed in the gut of Parkinson's disease patients, suggesting a potential role in disease initiation. Importantly, individuals with vagotomy have a reduced Parkinson's disease risk. From these observations, researchers have hypothesized that α-synuclein accumulation may initiate in the gut and subsequently propagate to the central dopaminergic neurons through the gut-brain axis, leading to Parkinson's disease. This review comprehensively examines the gut's involvement in Parkinson's disease, focusing on the concept of a gut-origin for the disease. We also examine the interplay between altered gut-related factors and the accumulation of pathological α-synuclein in the gut of Parkinson's disease patients. Given the accessibility of the gut to both dietary and pharmacological interventions, targeting gut-localized α-synuclein represents a promising avenue for developing effective Parkinson's disease therapies.

Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by motor impairment, resulting from the accumulation of α-synuclein and neuronal cell death in the substantia nigra of the midbrain. Emerging evidence suggests that α-synuclein aggregation may originate in the enteric nervous system (ENS) and subsequently propagate to the brain via the vagus nerve. Clinical observations, such as prodromal gastrointestinal dysfunction in PD patients and the increased incidence of PD among individuals with inflammatory bowel disease, support the hypothesis that abnormal intestinal inflammation may contribute to the onset of motor dysfunction and neuropathology in PD. This review examines recent findings on the interplay between intestinal immune cells and α-synuclein aggregation within the framework of gut-originated PD pathogenesis. It begins by discussing evidence linking dysbiosis and intestinal inflammation to α-synuclein aggregation in the ENS. Additionally, it explores the potential role of intestinal immune cells in influencing enteric neurons and α-synuclein aggregation, furthering the understanding of PD development.

A role of the immune system in Parkinson's disease (PD) progression has long been suspected due to the increased frequency of activated glial cells and infiltrating T cells in the substantia nigra. It was previously reported that PD donors have increased T cell responses towards PINK1 and α-synuclein (α-syn), two Lewy body-associated proteins. Further, T cell reactivity towards α-syn was highest closer to disease onset, highlighting that autoreactive T cells might play a role in PD pathogenesis. However, whether T cell autoreactivity is present during prodromal PD is unknown. Here, we investigated T cell responses towards PINK1 and α-syn in donors at high risk of developing PD (i.e. prodromal PD: genetic risk, hyposmia, and or REM sleep behavior disorder), in comparison to PD and healthy control donors. T cell reactivity to these two autoantigens was detected in prodromal PD at levels comparable to those detected in individuals with clinically diagnosed PD. Aligned with the increased incidence of PD in males, we found that males with PD, but not females, had elevated T cell reactivity compared to healthy controls. However, among prodromal PD donors, males and females had elevated T cell responses. These differing trends in reactivity highlights the need for further studies of the impact of biological sex on neuroinflammation and PD progression.

Parkinson's disease is the second most common neurodegenerative disorder and fastest growing neurological condition worldwide, yet its etiology and progression remain poorly understood. This disorder is characterized pathologically by the prion-like spread of misfolded neuronal alpha-synuclein proteins in specific brain regions leading to Lewy body formation, neurodegeneration, and progressive neurological impairment. It is unclear what triggers Parkinson's and where α-synuclein protein aggregation begins, although proposed induction sites include the olfactory bulb and dorsal motor nucleus of the vagus nerve. Within the last 20 years, there has been increasing evidence that Parkinson's could be triggered by early microbiome changes and α-synuclein accumulation in the gastrointestinal system. Gut microbiota dysbiosis that alters gastrointestinal motility, permeability, and inflammation could enable prion-like spread of α-synuclein from the gut-to-brain via the enteric nervous system. Individuals with isolated rapid eye movement sleep behavior disorder have a high likelihood of developing Parkinson's and might represent a prodromal 'gut-first' subtype of the condition. The gut-first model of Parkinson's offers novel gut-based therapeutic avenues, such as anti-, pre-, and pro-biotic preparations and fecal microbiota transplants. Crucially, gut-based interventions offer an avenue to treat Parkinson's at early prodromal stages with the aim of mitigating evolution to clinically recognizable Parkinson's disease characterized by motor impairment.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and one of the world's fastest-growing neurological diseases. Although the exact causes of PD are unknown, mitochondrial dysfunction and inflammation may have significant roles in disease progression. As well as being prevalent in the brain, there is also evidence that peripheral mitochondrial dysfunction and inflammation occur in PD. However, if/how peripheral mitochondrial dysfunction and inflammation are linked is still unclear.

This study aimed to determine the extent that mitochondrial dysfunction in peripheral immune cells is associated with inflammation in PD.

The study comprised of 35 controls and 35 PD patients that were age and sex matched. Flow cytometry was used to assess mitochondrial content and superoxide production in mononuclear cells, in the presence and absence of the mitochondrial stressor antimycin A. Serum inflammatory cytokines were measured by ELISA.

Superoxide levels were significantly increased in PD patient mononuclear cells at baseline, and PD mononuclear cells had an impaired response to antimycin A. Immune cell superoxide levels correlated with serum cytokines associated with T-cell responses, namely interleukin (IL) IL-12, interferon-γ, and IL-17A.

Results show that mitochondrial dysfunction is prevalent in PD immune cells and may contribute to an inflammatory phenotype. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The motor stage of Parkinson's disease (PD) can be preceded for years by a prodromal stage characterized by non-motor symptoms like REM sleep behavior disorder (RBD), hyposmia, and constipation. Here, we show that multiple stages of idiopathic PD, including the pre-motor prodromal stage, can be stratified according to the inflammatory responses to stimulation of peripheral blood mononuclear cells ex vivo. IFNγ stimulation of isolated monocytes reveals increased stimulation-dependent secretion of TNF, IL-1β, and IL-8 in prodromal PD relative to moderate stage PD. Additionally, T cells stimulated with CD3/CD28 co-stimulatory beads show diminished proinflammatory cytokine secretion in early-moderate PD relative to prodromal. Receiver operating characteristic curves demonstrate that several cytokines produced by stimulated monocytes show high predictive utility for distinguishing prodromal PD individuals from neurologically healthy controls. Moreover, immune stimulation reveals deficits in CD8+ T-cell mitochondrial health in moderate PD, with relative mitochondrial health in CD8+ T cells being positively correlated with stimulation-dependent secretion of IL-1β, IL-8, and IL-10 in T cells from prodromal PD subjects. Dysregulated mitochondrial health in immune cells may contribute to peripheral inflammation and PD progression, and ex vivo stimulation-based assays have the potential to reveal novel biomarkers for patient stratification and progression with immune endophenotypes.

Neuroinflammation is a key feature of Parkinson's disease (PD). The cannabinoid receptor type 2 (CB2R) is expressed by cells of the innate and adaptive immune systems. Inhibition of monoacylglycerol lipase (MAGL) with JZL184 increases the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG), which is neuroprotective for dopaminergic neurons. The aim of this study was to determine whether the neuroprotective effect of MAGL inhibition is mediated by CB2R activation on specific immune cell populations. Experimental parkinsonism was induced by chronic administration of MPTP and probenecid. A specific increase in CD4+ T cell infiltration was detected in the midbrain of parkinsonian mice and was reduced by administration of JZL184. JZL184 had no effect in CB2R KO mice, suggesting that CB2R is required for neuroprotection. In the brain, CB2R expression was restricted to myeloid cells and lymphocytes, and increased in microglia under parkinsonian conditions. Administration of a central CB2R agonist, JWH133, exerted a beneficial effect similar to that of JZL184, whereas the peripheral agonist RO304 lacked neuroprotective activity. These results were confirmed using chimeric mice. In silico analysis, showed that transcripts related to 2-AG biosynthesis are downregulated in the midbrain microglia from PD patients. Our results show that activation of CB2R in the brain prevents nigrostriatal degeneration, CD4+ T cell infiltration and TNFα production in the midbrain of parkinsonian mice. The reduced 2-AG signaling in microglia from PD patients suggests that activation of microglial CB2R may be an interesting strategy for the treatment of PD.

Several therapies, including sphingosine 1-phosphate receptor modulators, have been approved for ulcerative colitis (UC). Safety findings should be complemented with real-world data (RWD) as rare events may be underestimated in clinical trials due to populations not fully reflecting real-world practice.

We used RWD to investigate safety outcomes in 4 cohorts: (1) those receiving any UC treatment (UC overall), (2) those receiving advanced therapies (UC advanced therapy), (3) those meeting the selection criteria of the etrasimod ELEVATE UC clinical program (UC trial-similar), (4) individuals without UC (Non-UC). Data were extracted (1/2016-12/2022) from the Optum® de-identified Electronic Health Record data set.

Data from 32 170 (UC overall), 3332 (UC advanced therapy), 1435 (UC trial-similar), and 160 795 (Non-UC) individuals were included. In the UC overall cohort, <11% of patients used advanced therapy. The UC overall cohort had significantly higher incidence rates (IRs) across most safety outcomes compared with the Non-UC cohort (highest: malignancy [excluding non-melanoma skin cancer] at 31.1 compared with 14.1 IRs per 1000 patient-years, respectively), regardless of age or oral corticosteroid use. Incidence rates of safety outcomes for the UC advanced therapy and UC trial-similar (also requiring prior advanced therapy use) cohorts were generally similar or lower than the UC overall cohort. The UC trial-similar and UC advanced therapy cohorts had generally comparable safety outcomes.

These findings assist in understanding the background risks of safety events in patients with UC and suggest that the incidence of select safety outcomes is comparable between the ELEVATE UC trials and RWD.

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, α-Synuclein (α-Syn) pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulate major histocompatibility complex class II (MHCII), and variants in genes encoding MHCII affect PD risk. Additionally, elevated TNF levels and α-Syn-reactive T cells in circulation suggest a strong link between innate and adaptive immune responses in PD. We have previously reported that reduced levels of the class II transactivator, the master regulator of MHCII expression, increases susceptibility to α-Syn-induced PD-like pathology in rats and are associated with higher serum levels of soluble TNF (sTNF). Here, we demonstrate that inhibiting sTNF with a dominant-negative TNF variant, XPro1595, known to be neuroprotective in endotoxin- and toxin-induced neurodegeneration models, fails to protect against robust α-Syn-induced PD-like pathology in rats. We used a model combining rAAV-mediated α-Syn overexpression in SNpc with striatal injection of α-Syn preformed fibrils two weeks later. Systemic XPro1595 treatment was initiated one-week post-rAAV-α-Syn. We observed up to 70 % loss of striatal dopaminergic fibers without treatment, and no protective effects on dopaminergic neurodegeneration after XPro1595 administration. Pathological α-Syn levels as well as microglial and astrocytic activation were not reduced in SNpc or striatum following XPro1595 treatment. An increase in IL-6 and IL-1β levels in CSF was observed in rats treated with XPro1595, possibly explaining a lack of protective effects following treatment. Our results highlight the need to determine the importance of timing of treatment initiation, which is crucial for future applications of sTNF therapies in PD patients.

The human gut microbiota is diverse and abundant and plays important roles in regulating health by participating in metabolism and controlling physiological activities. The gut microbiota and its metabolites have been shown to affect the functioning of the gut and central nervous system through the microbiota-gut-brain axis. It is well established that microbiota play significant roles in the pathogenesis and progression of Parkinson's disease (PD). Disorders of the intestinal microbiota and altered metabolite levels are closely associated with PD. Here, the changes in intestinal microbiota and effects of metabolites in patients with PD are reviewed. Potential mechanisms underlying intestinal microbiota disorders in the pathogenesis of PD are briefly discussed. Additionally, we outline the current strategies for the treatment of PD that target the gut microbiota, emphasizing the development of promising novel strategies.

Mitochondria are key regulators of inflammatory responses and mitochondrial dysfunction is closely linked to various inflammatory diseases. Increasing genetic and experimental evidence suggests that mitochondria play a critical role in inflammatory bowel disease (IBD). In the complex environment of the intestinal tract, intestinal epithelial cells (IECs) and their mitochondria possess unique phenotypic features, shaping each other and regulating intestinal homeostasis and inflammation through diverse mechanisms. Here, we focus on intestinal inflammation in IBD induced by mitochondrial damage-associated molecular patterns (mtDAMPs), which comprise mitochondrial components and metabolic products. The pathogenic mechanisms of mtDAMP signaling pathways mediated by two major mtDAMPs, mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (mtROS), are discussed.

Psoriasis is genetically influenced and can be triggered by factors such as infections, stress, and lifestyle. Chronic plaque psoriasis, the most prevalent form, involves key roles for IL-17 and IL-23 in its pathogenesis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness and atrophy. Currently, there is no cure for ALS, and treatment is symptomatic, aimed at improving quality of life. The combination of psoriasis and ALS is relatively rare. Although biologic agents have shown remarkable efficacy in the treatment of chronic plaque psoriasis, we have not found any case reports regarding the use of biologic agents for treating psoriasis accompanied by ALS. Our study presents a patient with severe plaque psoriasis and ALS who exhibited a positive response to Guselkumab, without worsening of ALS symptoms, suggesting a promising therapeutic strategy. This could provide a treatment option for patients with psoriasis combined with ALS.We conducted a comprehensive review of the literature on the comorbidity of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ALS, with plaque psoriasis. This review highlights the differential impact of treatment modalities. Specifically, we found that TNF-α inhibitors may have adverse effects in MS but could provide protective benefits in AD and PD. In ALS patients with psoriasis, IL-17A and IL-23 inhibitors, exemplified by Guselkumab, are suggested as a more suitable alternative due to their lower risk of worsening ALS symptoms.

Constitutive activation of STING by gain-of-function mutations triggers manifestation of the systemic autoinflammatory disease STING-associated vasculopathy with onset in infancy (SAVI). In order to investigate the role of signaling by tumor necrosis factor (TNF) in SAVI, we used genetic inactivation of TNF receptors 1 and 2 in murine SAVI, which is characterized by T cell lymphopenia, inflammatory lung disease, and neurodegeneration. Genetic inactivation of TNFR1 and TNFR2, however, rescued the loss of thymocytes, reduced interstitial lung disease, and neurodegeneration. Furthermore, genetic inactivation of TNFR1 and TNFR2 blunted transcription of cytokines, chemokines, and adhesions proteins, which result from chronic STING activation in SAVI mice. In addition, increased transendothelial migration of neutrophils was ameliorated. Taken together, our results demonstrate a pivotal role of TNFR signaling in the pathogenesis of SAVI in mice and suggest that available TNFR antagonists could ameliorate SAVI in patients.

Parkinson's disease (PD) is a common neurodegenerative disorder with increasing incidence and disability rates globally, placing a heavy burden on patients and their families. In the prodromal phase of PD, nonmotor symptoms, particularly depression and sleep disorders, are frequent, with profound effects on disease progression and patient quality of life. Emerging research highlights the critical role of inflammatory markers-including interleukins and tumor necrosis factor-in the pathogenesis of prodromal PD. These inflammatory mediators participate in neurodegenerative processes and may induce or exacerbate depressive symptoms and sleep disorders by disrupting the function of the hypothalamic-pituitary-adrenal axis and affecting neurotransmitter, including serotonin, metabolism. Understanding their correlations with nonmotor symptoms in prodromal PD remains incomplete, limiting our ability to develop targeted interventions. This comprehensive review aims to investigate the specific correlations between inflammatory markers and nonmotor symptoms-particularly depression and sleep disorders-in prodromal PD. The findings could have important practical applications, potentially leading to the development of new diagnostic tools and therapeutic strategies for managing PD. By identifying and understanding these correlations, healthcare providers may better predict disease progression and implement more effective treatments for nonmotor symptoms in PD.

Epidemiological studies reveal that inflammatory bowel disease (IBD) is associated with an increased risk of Parkinson's disease (PD). Gut dysbiosis has been documented in both PD and IBD, however it is currently unknown whether gut dysbiosis underlies the epidemiological association between both diseases. To identify shared and distinct features of the PD and IBD microbiome, we recruited 54 PD, 26 IBD, and 16 healthy control individuals and performed the first joint analysis of gut metagenomes. Larger, publicly available PD and IBD metagenomic datasets were also analyzed to validate and extend our findings. Depletions in short-chain fatty acid (SCFA)-producing bacteria, including Roseburia intestinalis, Faecalibacterium prausnitzii, Anaerostipes hadrus, and Eubacterium rectale, as well depletion in SCFA-synthesis pathways were detected across PD and IBD datasets, suggesting that depletion of these microbes in IBD may influence the risk for PD development.

The disruption of microglial homeostasis and cytokine release are critical for neuroinflammation post-injury and strongly implicated in retinal neurodegenerative diseases like glaucoma. This study examines microglial responses to chemical hypoxia induced by cobalt chloride (CoCl2) in BV-2 murine microglial cells, focusing on signaling pathways and proteomic alterations. We assessed the protective effects of monoclonal antibodies against TNFα and IL-1β. CoCl2 exposure led to decreased cell viability, reduced mitochondrial membrane potential, increased lactate dehydrogenase release, elevated reactive oxygen species generation, and activation of inflammatory pathways, including nitric oxide synthase (iNOS), STAT1, and NF-κB/NLRP3. These responses were significantly mitigated by treatment with anti-TNFα and anti-IL-1β, suggesting their dual role in reducing microglial damage and inhibiting inflammatory reactivity. Additionally, these treatments reduced apoptosis by modulating ATF4 and the p38 MAPK/caspase-3 pathways. Label-free quantitative mass spectrometry-based proteomics and Gene Ontology revealed that CoCl2 exposure led to the upregulation of proteins primarily involved in endoplasmic reticulum and catabolic processes, while downregulated proteins are associated with biosynthesis. Anti-TNFα and anti-IL-1β treatments partially restored the proteomic profile toward normalcy, with network analysis identifying heat shock protein family A member 8 (HSPA8) as a central mediator in recovery. These findings offer insights into the pathogenesis of hypoxic microglial impairment and suggest potential therapeutic targets.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and nonmotor dysfunctions. Its pathological hallmark is the aggregation of ɑ-synuclein in the central nervous system (CNS), leading to widespread loss of dopaminergic neurons in the substantia nigra (SN). Interestingly, metabolic disorders localized in the periphery, such as diabetes mellitus, frequently co-occur with PD. Emerging evidence highlights a bidirectional relationship: metabolic diseases may accelerate PD progression, while PD can exacerbate metabolic dysfunction. Beyond these associations, a growing body of research suggests that dysfunction in the peripheral nervous system, the primary communication bridge between the brain and peripheral organs, plays a critical role in these comorbidities. Autonomic nerve perturbation may accelerate dopaminergic neuronal loss in the SN and exacerbate metabolic dysregulation. This chapter synthesizes current evidence linking autonomic dysfunction with the progression of PD and related metabolic disorders, and it explores innovative therapeutic strategies leveraging this bidirectional relationship to address PD progression.

Neuroprotective therapy to slow Parkinson's disease (PD) progression is a critical unmet need. Neuroinflammation likely represents an important pathophysiologic mechanism for disease progression. Medications that target this inflammation, such as immunosuppressants, represent potential disease-modifying therapies for PD. The relation between these medications and PD risk might inform candidate selection.

We conducted a population-based case-control study using Medicare data from the United States. The study included 207,532 incident PD cases and 975,177 controls from 2016 to 2018, age 67-110. We examined the association between PD risk and immunosuppressant use before PD diagnosis/control selection. We considered 37 immunosuppressants, representing >10 medication classes, in Part D prescription claims. We used logistic regression to estimate the relative risk (RR) and 95 % confidence interval (CI) between each medication and PD, while accounting for age, sex, race/ethnicity, smoking, and healthcare utilization. In sensitivity analyses we applied exposure lagging, restricted to immunosuppressant users, and corrected for multiple comparisons.

Medicare beneficiaries using the calcineurin inhibitor tacrolimus (RR 0.49, CI 0.40-0.60) and mTOR inhibitors everolimus (RR 0.38, CI 0.26-0.56) and sirolimus (RR 0.59, CI 0.37-0.93) had a lower risk of PD compared to those not taking the medication. The TNF inhibitor certolizumab was also associated with lower PD risk (RR 0.54, CI 0.34-0.84). Tacrolimus and everolimus remained significant after Bonferroni correction. Sensitivity analyses otherwise confirmed results for all four medications.

Calcineurin or mTOR inhibition might reduce PD risk. Future studies should examine whether these medications or structurally similar agents might have potential as disease-modifying therapies for PD.

Emerging evidence suggests that systemic inflammation may play a critical role in neurological disorders. Recent studies have shown the connection between inflammatory bowel diseases (IBD) and neurological disorders, revealing a bidirectional relationship through the gut-brain axis. Immunotherapies, such as Treg cells infusion, have been proposed for IBD. However, the role of adaptive immune cells in IBD-induced neuroinflammation remains unclear. In this study, we established an animal model for IBD in mice with severe combined immune-deficient (SCID), an adaptive immune deficiency, to investigate the role of adaptive immune cells in IBD-induced neuroinflammation. Mice were fed 1%, 3%, or 5% dextran sulfate sodium (DSS) for 5 days. We measured body weight, colon length, disease activity index (DAI), and crypt damage. Pro-inflammatory cytokines were measured in the colon, while microglial morphology, neuronal count, and inflammatory cytokines were analyzed in the brain. In the 3% DSS group, colitis symptoms appeared at day 7, with reduced colon length and increased crypt damage showing colitis-like symptoms. By day 21, colon length and crypt damage persisted, while DAI showed recovery. Although colonic inflammation peaked at day 7, no significant increase in inflammatory cytokines or microglial hyperactivation was observed in the brain. By day 21, neuroinflammation was detected, albeit with a slight delay, in the absence of adaptive immune cells. The colitis-induced neuroinflammation model provides insights into the fundamental immune mechanisms of the gut-brain axis and may contribute to developing immune cell therapies for IBD-induced neuroinflammation.

Background: Parkinson's disease (PD) is intricately linked to gastrointestinal inflammation and the presence of neurotoxins in the gut, integrating α-syn pathologic alterations and subsequent neurodegeneration into the brain. Objectives: This study aimed to explore the enduring impact of dextran sodium sulfate (DSS)-mediated colitis on the vulnerability of central dopaminergic neurons to subsequent rotenone exposure. Methods: To induce chronic colitis, 10-month-old C57BL/6 mice were pre-exposed to 3 cycles of 1 week of 1% (w/v) DSS administration in drinking water followed by 2 weeks of regular drinking water. After colitis induction, animals received a low dose of intragastric rotenone for the next 8 weeks, followed by testing for Parkinsonian behavior and GI phenotypes of inflammation. At the end of the 17th week, colon, brain stem, and midbrain tissue were isolated and analyzed for α-syn, inflammatory markers, and dopaminergic neuronal loss. Gut microbial composition was assessed by 16S rRNA sequencing analysis. Results: We found that chronic rotenone administration in the presence of preexisting colitis led to a further increase in colonic pro-inflammatory mediator expressions, α-syn expression, and reduced colonic tight junction protein expressions. We also found early impairment of GI functions and worsened grip strength in rotenone-exposed colitic mice. Furthermore, α-syn pathology specific to the colitic mice exposed to rotenone showed dopaminergic neurons degeneration and astroglial activation in substantia nigra and striatum, including regions of the brain stem, i.e., dorsal motor of the vagus and locus coeruleus. Finally, the result of 16S rRNA gene sequencing analysis indicated that colitic mice, after being exposed to rotenone, exhibited a discernible trend in their microbiota composition (Catenibacterium, Turicibactor, and clostridium sensue stricto 1), linking it to the development of PD. Conclusions: These findings indicate that prolonged low-dose rotenone exposure, combined with an early inflammatory intestinal milieu, provides a preconditioning effect on α-syn pathology and exerts neurodegeneration in the intragastric rotenone PD mouse model.

Emerging evidence suggests that dysbiosis of the gut microbiota is associated with the pathogenesis of Parkinson's disease (PD), a prevalent neurodegenerative disorder. The microbiota-gut-brain axis plays a crucial role in the development and progression of PD, and numerous studies have demonstrated the potential therapeutic benefits of modulations in the intestinal microbiota. This review provides insights into the characterization of the gut microbiota in patients with PD and highlights associations with clinical symptoms and underlying mechanisms. The discussion underscores the increased influence of the gut microbiota in the pathogenesis of PD. While the relationship is not fully elucidated, existing research demonstrates a strong correlation between changes in the composition of gut microbiota and disease development, and further investigation is warranted to explain the specific underlying mechanisms.

The review discusses the influence of various factors (e.g., post-translational modifications and chaperones) on the pathological transformation of amyloidogenic proteins involved in the onset and development of neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and spongiform encephalopathies of various origin with special focus on the role of α-synuclein, prion protein, and, to a lesser extent, beta-amyloid peptide. The factors investigated by the authors of this review are discussed in more detail, including posttranslational modifications (glycation and S-nitrosylation), cinnamic acid derivatives and dendrimers, and chaperonins (eukaryotic, bacterial, and phage). A special section is devoted to the role of the gastrointestinal microbiota in the pathogenesis of amyloid neurodegenerative diseases, in particular, its involvement in the transformation of infectious prions and possibly other proteins capable of prion-like transmission of amyloidogenic diseases.

Increasing evidence indicates the mechanism of overlapping immune dysfunction and inflammation disorder shared by ankylosing spondylitis (AS) and neurodegenerative diseases (NDs). However, the exact correlation between the two is still unclear. Different studies have reported inconsistent results about how AS and NDs are related.

This study aimed to investigate the association between AS and risk of NDs.

We searched electronic databases including PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials to identify studies reporting relationship between NDs risk and AS published before April 10th, 2024. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were estimated. All analyses were conducted using Stata V.12.0 software.

A total of 15 comparisons out of 10 studies involving 851,936 participants were included. The results showed that the risk of NDs was higher among AS patients than those who were not (OR: 1.36, 95% CI: 1.15-1.60, P<0.001). In addition, subgroup analysis showed that AS was associated with an increased risk of Parkinson's disease (PD) development (OR: 1.55, 95% CI: 1.31-1.83, P<0.001), whereas there is no observed association with Alzheimer's disease (AD) and dementia (OR: 1.22, 95% CI: 0.96-1.55, P=0.098; OR: 1.34, 95% CI: 0.96-1.87, P=0.089, respectively).

The current meta-analysis identified AS as a risk factor for the development of NDs. Clinicians should be aware of the potential association between these diseases. Further research is necessary to confirm the causal relationship and underlying mechanisms between AS and NDs.

Gut inflammation is a salient prodromal feature of Parkinson's disease (PD) implicated in pathologic processes leading to nigrostriatal dopaminergic degeneration. However, existing rodent models of PD are suboptimal for investigating the interaction between gut inflammation and neuropathology. This study aimed to develop a rat model of PD in which gut inflammation exacerbated PD symptoms induced by a parkinsonian lesion. This was achieved by combining the 6-hydroxydopamine (6-OHDA) rat model for PD and the dextran sodium sulfate (DSS) rat model for colitis. The model was characterised using behavioural tests, including reaching, step, gait, open-field and cylinder tests, plus stereological quantification of substantia nigra (SN) DA neurodegeneration, and histological analysis of SN microglial activation and distal colon morphology. The combination of 6-OHDA and DSS resulted in greater stool softening and bleeding, shorter colons and greater distal colon histological damage, when compared with the 6-OHDA model. Additionally, 6-OHDA and DSS rats displayed similar DA neurodegeneration, yet less SN microglial activation, when compared to 6-OHDA rats that did not receive DSS. Finally, DSS + 6-OHDA rats exhibited impaired forelimb motor function compared with 6-OHDA rats, with decreased performance in reaching and step tests. In conclusion, DSS administration exacerbated forelimb motor dysfunction in 6-OHDA rats. Behavioural changes in DSS + 6-OHDA rats were associated with lower levels of microglial activation and similar levels of dopamine depletion compared with 6-OHDA-only rats. These results support that the DSS + 6-OHDA rat model is a promising PD animal model to investigate deleterious gut-brain interactions in PD.

The human mycobiome encompasses diverse communities of fungal organisms residing within the body and has emerged as a critical player in shaping health and disease. While extensive research has focused on the skin and gut mycobiome, recent investigations have pointed toward the potential role of fungal organisms in neurological disorders. Among those fungal organisms, the presence of the commensal fungus Malassezia in the brain has created curiosity because of its commensal nature and primary association with the human skin and gut. This budding yeast is responsible for several diseases, such as Seborrheic dermatitis, Atopic dermatitis, Pityriasis versicolor, Malassezia folliculitis, dandruff, and others. However recent findings surprisingly show the presence of Malassezia DNA in the brain and have been linked to diseases like Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. The exact role of Malassezia in these disorders is unknown, but its ability to infect human cells, travel through the bloodstream, cross the blood-brain barrier, and reside along with the lipid-rich neuronal cells are potential mechanisms responsible for pathogenesis. This also includes the induction of pro-inflammatory cytokines, disruption of the blood-brain barrier, gut-microbe interaction, and accumulation of metabolic changes in the brain environment. In this review, we discuss these key findings from studies linking Malassezia to neurological disorders, emphasizing the complex and multifaceted nature of these cases. Furthermore, we discuss potential mechanisms through which Malassezia might contribute to the development of neurological conditions. Future investigations will open up new avenues for our understanding of the fungal gut-brain axis and how it influences human behavior. Collaborative research efforts among microbiologists, neuroscientists, immunologists, and clinicians hold promise for unraveling the enigmatic connections between human commensal Malassezia and neurological disorders.

The motor stage of idiopathic Parkinson's disease (iPD) can be preceded for years by a prodromal stage characterized by non-motor symptoms like REM sleep behavior disorder (RBD). Here, we show that multiple stages of iPD, including the pre-motor prodromal stage, can be stratified according to the inflammatory and immunometabolic responses to stimulation of peripheral blood mononuclear cells ex vivo. We identified increased stimulation-dependent secretion of TNF, IL-1β, and IL-8 in monocytes from RBD patients and showed diminished proinflammatory cytokine secretion in monocytes and T cells in early and moderate stages of PD. Mechanistically, immune activation revealed deficits in CD8+ T-cell mitochondrial health in moderate PD, and relative mitochondrial health in CD8+ T cells was positively correlated with stimulation-dependent T-cell cytokine secretion across the PD spectrum. Dysregulated immunometabolism may drive peripheral inflammation and PD progression, and ex vivo stimulation-based assays have potential to reveal novel biomarkers for patient stratification and progression with immune endophenotypes.

We study the clinical value of peripheral blood immunoglobulin G (IgG) and immunoglobulin M (IgM) combined with ultrasonic echo parameters of substantia nigra (SN) in the diagnosis of Parkinson's disease (PD). The clinical data of 121 patients with PD (case group) in our hospital from November 2020 to November 2022 were selected for retrospective analysis, and 9 patients with poor sound transmission of temporal window were excluded. Finally, this study included 112 patients with PD and selected 108 health examination population in the same period (control group). The levels of IgG and IgM in both groups were detected, and ultrasound examination was carried out to observe the structure of SN and obtain strong echo area of SN, midbrain area and strong echo area of SN/midbrain area. The receiver operator characteristic curve of serum IgG and IgM combined with ultrasonic echo parameters of SN in the diagnosis of PD was drawn to evaluate the clinical efficacy of single diagnosis and combined diagnosis. Compared with the control group, the serum levels of IgG and IgM, strong echo area of SN, midbrain area and strong echo area of SN/midbrain area in the case group were obviously higher (P < 0.001), while the folic acid level was notably lower (P < 0.05). The AUC value, Youden index and sensitivity of combined diagnosis were higher than those of single detection. Peripheral blood IgG and IgM combined with ultrasonic echo parameters of SN have high clinical value in the diagnosis of PD, which can provide a new direction for the subsequent diagnosis of PD.

Previous research suggests shared pathophysiology between Parkinson's Disease (PD) and autoimmune disorders, with inflammation reduction as a potential PD intervention. The impact of anti-tumor necrosis factor (anti-TNF) and anti-interleukin (IL)-17 drugs on PD development has yielded conflicting results.

The study investigated the association between PD incidence and immunosuppressive anti-inflammatory drugs in patients with autoimmune diseases (rheumatoid arthritis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, psoriasis/psoriatic arthritis).

A retrospective study was conducted using data from 2014 to 2022 from the US Komodo Health claims database. Two cohorts of patients diagnosed with autoimmune diseases were designed: 1) exposed to biologic disease-modifying antirheumatic drugs (bDMARDS e.g., anti-TNF/anti-IL-17 drugs) and 2) absent such exposure. Person-time incidence rates of PD per 100 person-years (PY) and incidence rate ratios (IRRs) were calculated and covariate adjusted via Poisson regressions.

Among 2,105,677 identified patients with autoimmune disease, 114,082 were treated with anti-TNF/anti-IL-17 and 1,991,595 were not. Unadjusted analyses indicated lower PD incidence in those treated with bDMARDscompared to the not treated (0.661 vs 0.949 per 100-PY; IRR 0.696 [95 % CI: 0.669-0.724]). Multivariate Poisson models comparing cohorts exposed to bDMARDs vs those lacking exposure resulted in significantly lower risk of PD (adjusted IRR 0.77 [95 % CI 0.74-0.80], p-value <0.0001). For patients exposed to anti-TNF or anti-IL-17 therapies, the IRRs were 0.77 (95 % CI 0.74-0.81) and 0.64 (95 % CI 0.52-0.80), respectively (p-values<0.001).

The results suggest that reduced systemic inflammation via anti-TNF or anti-IL-17 treatment may decrease PD risk in patients with autoimmune diseases.

Pro-inflammatory cytokines are emerging as neuroinflammatory mediators in Parkinson's disease (PD) due to their ability to act through neuronal cytokine receptors. Critical questions persist regarding the role of cytokines in neuronal dysfunction and their contribution to PD pathology. Specifically, the potential synergy of the hallmark PD protein alpha-synuclein (α-syn) with cytokines is of interest. We therefore investigated the direct impact of pro-inflammatory cytokines on neurons and hypothesized that α-syn pathology exacerbates cytokine-induced neuronal deficits in PD. iPSC-derived cortical neurons (CNs) from healthy controls and patients with α-syn gene locus duplication (SNCA dupl) were stimulated with IL-17A, TNF-α, IFN-γ, or a combination thereof. For rescue experiments, CNs were pre-treated with α-syn anti-oligomerisation compound NPT100-18A prior to IL-17A stimulation. Cytokine receptor expression, microtubule cytoskeleton, axonal transport and neuronal activity were assessed. SNCA dupl CNs displayed an increased IL-17A receptor expression and impaired IL-17A-mediated cytokine receptor regulation. Cytokines exacerbated the altered distribution of tubulin post-translational modifications in SNCA dupl neurites, with SNCA dupl-specific IL-17A effects. Tau pathology in SNCA dupl CNs was also aggravated by IL-17A and cytokine mix. Cytokines slowed down mitochondrial axonal transport, with IL-17A-mediated retrograde slowing in SNCA dupl only. The pre-treatment of SNCA dupl CNs with NPT100-18A prevented the IL-17A-induced functional impairments in axonal transport and neural activity. Our work elucidates the detrimental effects of pro-inflammatory cytokines, particularly IL-17A, on human neuronal structure and function in the context of α-syn pathology, suggesting that cytokine-mediated inflammation represents a second hit to neurons in PD which is amenable to disease modifying therapies that are currently in clinical trials.

Microglia, the resident immune cells of the brain, regulate the balance of inflammation in the central nervous system under healthy and pathogenic conditions. Huntington's disease (HD) is a chronic neurodegenerative disease characterized by activated microglia and elevated concentrations of pro-inflammatory cytokines within the brain. Chronic hyperactivation of microglia is associated with brain pathology and eventual neuron death. However, it is unclear which specific cytokines are required for neuron death and whether HD neurons may be hypersensitive to neuroinflammation. We assessed the profile of microglia-secreted proteins in response to LPS and IFNγ, and a conditioned media paradigm was used to examine the effects of these secreted proteins on cultured neuronal cells. STHdhQ7/Q7 and STHdhQ111/Q111 neuronal cells were used to model wild-type and HD neurons, respectively. We determined that STHdhQ111/Q111 cells were hypersensitive to pro-inflammatory factors secreted by microglia, and that TNF was required to induce neuronal death. Microglia-mediated neuronal death could be effectively halted through the use of JAK-STAT or TNF inhibitors which supported the requirement for TNF as well as IFNγ in the process of secondary neurotoxicity. Further data derived from human HD patients as well as HD mice were suggestive of enhanced receptor density for TNF (TNFR1) and IFNγ (IFNGR) which could sensitize the HD brain to these cytokines. This highlights several potential mechanisms by which microglia may induce neuronal death and suggests that these mechanisms may be upregulated in the brain of HD patients.

Recent experimental and clinical data demonstrate a significant dysregulation of the gut microbiome in individuals with Parkinson's disease (PD). With an immense influence on all aspects of physiology, this dysregulation has potential to directly or indirectly contribute to disease pathology. Experimental models have bridged these associations toward defined contributions, identifying various microbiome-dependent impacts to PD pathology. These studies have laid the foundation for human translation, examining whether certain members of the microbiome and/or whole restoration of the gut microbiome community can provide therapeutic benefit for people living with PD. Here, we review recent and ongoing clinically-focused studies that use microbiome-targeted therapies to limit the severity and progression of PD. Fecal microbiome transplants, prebiotic interventions, and probiotic supplementation are each emerging as viable methodologies to augment the gut microbiome and potentially limit PD symptoms. While still early, the data in the field to date support continued cross-talk between experimental systems and human studies to identify key microbial factors that contribute to PD pathologies.

Cognitive deficits are a common comorbidity with neurological disorders and normal aging. Inflammation is associated with multiple diseases including classical neurodegenerative dementias such as Alzheimer's disease (AD) and autoimmune disorders such as multiple sclerosis (MS), in which over half of all patients experience some form of cognitive deficits. Other degenerative diseases of the central nervous system (CNS) including frontotemporal lobe dementia (FTLD), and Parkinson's disease (PD) as well as traumatic brain injury (TBI) and psychological disorders like major depressive disorder (MDD), and even normal aging all have cytokine-associated reductions in cognitive function. Thus, there is likely commonality between these secondary cognitive deficits and inflammation. Neurological disorders are increasingly associated with substantial neuroinflammation, in which CNS-resident cells secrete cytokines and chemokines such as tumor necrosis factor (TNF)α and interleukins (ILs) including IL-1β and IL-6. CNS-resident cells also respond to a wide variety of cytokines and chemokines, which can have both direct effects on neurons by changing the expression of ion channels and perturbing electrical properties, as well as indirect effects through glia-glia and immune-glia cross-talk. There is significant overlap in these cytokine and chemokine expression profiles across diseases, with TNFα and IL-6 strongly associated with cognitive deficits in multiple disorders. Here, we review the involvement of various cytokines and chemokines in AD, MS, FTLD, PD, TBI, MDD, and normal aging in the absence of dementia. We propose that the neuropsychiatric phenotypes observed in these disorders may be at least partially attributable to a dysregulation of immunity resulting in pathological cytokine and chemokine expression from both CNS-resident and non-resident cells.

Clonal hematopoiesis of indeterminate potential (CHIP), a premalignant expansion of mutated hematopoietic stem cells, is linked to immune alterations. Given the role of neuroinflammation and immune dysfunction in Parkinson's disease (PD), we hypothesized a connection between CHIP and PD. We analyzed peripheral blood DNA from 341 PD, 92 isolated REM sleep behavior disorder (iRBD) patients, and 5003 controls using targeted sequencing of 24 genes associated with hematologic neoplasms. PD cases were classified by clinical progression mode: fast, slow, and typical. Using multivariable logistic regression models, CHIP prevalence was assessed against controls with a 1.0% variant allele fraction threshold. CHIP with TET2 mutations was more prevalent in PD than controls (aOR 1.75, 95% CI 1.11-2.77, p = 0.017), particularly in the fast motor progression subgroup (aOR 3.19, p = 0.004). No distinct associations were observed with iRBD. PD is linked to increased odds of CHIP with TET2 mutations, suggesting immune dysregulation in PD pathophysiology.

Desulfovibrio, resident gut sulfate-reducing bacteria (SRB), are found to overgrow in diseases such as inflammatory bowel disease and Parkinson's disease. They activate a pro-inflammatory response, suggesting that Desulfovibrio may play a causal role in inflammation. Class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway regulates key events in the inflammatory response to infection. Dysfunctional PI3K/Akt signaling is linked to numerous diseases. Bacterial-induced PI3K/Akt pathway may be activated downstream of toll-like receptor (TLR) signaling. Here, we tested the hypothesis that Desulfovibrio vulgaris (DSV) may induce tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) expression via PI3K/Akt in a TLR 2-dependent manner. RAW 264.7 macrophages were infected with DSV, and protein expression of p-Akt, p-p70S6K, p-NF-κB, p-IkB, TNF-α, and iNOS was measured. We found that DSV induced these proteins in a time-dependent manner. Heat-killed and live DSV, but not bacterial culture supernatant or a probiotic Lactobacillus plantarum, significantly caused PI3K/AKT/TNF/iNOS activation. LY294002, a PI3K/Akt signaling inhibitor, and TL2-C29, a TLR 2 antagonist, inhibited DSV-induced PI3K/AKT pathway. Thus, DSV induces pro-inflammatory TNF-α and iNOS via PI3K/Akt pathway in a TLR 2-dependent manner. Taken together, our study identifies a novel mechanism by which SRB such as Desulfovibrio may trigger inflammation in diseases associated with SRB overgrowth.

Parkinson's disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of α-synuclein (α-Syn) into insoluble aggregates called Lewy pathology. The Line 61 α-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human α-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human α-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-α-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-α-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.

Neurodegenerative diseases represent a huge healthcare challenge which is predicted to increase with an aging population. Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), present complex challenges in understanding their onset and progression. They are characterized by the abnormal aggregation of α-synuclein in the brain leading to neurodegeneration. Accumulating evidence supports the existence of distinct subtypes based on the site of α-synuclein aggregation initiation, genetics, and, more recently, neuroinflammation. Mediated by both central nervous system-resident cells, peripheral immune cells, and gut dysbiosis, neuroinflammation appears as a key process in the onset and progression of neuronal loss. Sex-based differences add another layer of complexity to synucleinopathies, influencing disease prevalence - with a known higher incidence of PD in males compared to females - as well as phenotype and immune responses. Biological sex affects neuroinflammatory pathways and the immune response, suggesting the need for sex-specific therapeutic strategies and biomarker identification. Here, we review the heterogeneity of synucleinopathies, describing the etiology, the mechanisms by which the inflammatory processes contribute to the pathology, and the consideration of sex-based differences to highlight the need for personalized therapeutics.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and its hallmark pathological features are the loss of dopaminergic (DA) neurons in the midbrain substantia nigra pars compacta (SNpc) and the accumulation of alpha-synuclein (α-syn). It has been shown that the integrity of the blood-brain barrier (BBB) is damaged in PD patients, and a large number of infiltrating T cells and inflammatory cytokines have been detected in the cerebrospinal fluid (CSF) and brain parenchyma of PD patients and PD animal models, including significant change in the number and proportion of different CD4+ T cell subsets. This suggests that the neuroinflammatory response caused by CD4+ T cells is an important risk factor for the development of PD. Here, we systematically review the differentiation of CD4+ T cell subsets, and focus on describing the functions and mechanisms of different CD4+ T cell subsets and their secreted cytokines in PD. We also summarize the current immunotherapy targeting CD4+ T cells with a view to providing assistance in the diagnosis and treatment of PD.

We review the epidemiologic literature on potential protective and risk factors in Parkinson's Disease (PD). Prior research identified numerous possible protective and risk factors. Potential protective factors include tobacco abuse, physical activity, urate levels, NSAID use, calcium channel blocker use, statin use, and use of some α1-adrenergic antagonists. Some potential protective factors could be products of reverse causation, including increased serum urate, tobacco abuse, and coffee-tea-caffeine consumption. Potential risk factors include traumatic brain injury, pesticide exposure, organic solvent exposure, lead exposure, air pollution, Type 2 Diabetes, some dairy products, cardiovascular disease, and some infections including Hepatitis C, H. pylori, and COVID-19. Potential non-environmental risk factors include bipolar disorder, essential tremor, bullous pemphigoid, and inflammatory bowel disease. There is an inverse relationship with PD and risk of most cancers. Though many potential protective and risk factors for PD were identified, research has not yet led to unique, rigorous prevention trials or successful disease-modifying interventions. While efforts to reduce exposure to some industrial toxicants are well justified, PD incidence might be most effectively reduced by mitigation of risks, such as Type 2 Diabetes, air pollution, traumatic brain injury, or physical inactivity, that are general public health intervention targets.

Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival in vivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclear factor κB (NF-κB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD.

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of dopaminergic neurons and neuroinflammation. Recent studies have identified a role of T cells in the pathogenesis of PD. Additionally, these studies suggested that α-synuclein (α-Syn) is related to abnormal T-cell responses and may act as an epitope and trigger autoimmune T-cell responses. However, it is unclear whether the α-Syn-mediated autoimmune response occurs and whether it is related to neuronal cell death and glial cell activation. In this study, we investigated the autoimmune T-cell response induced by α-Syn peptides and evaluated the neurotoxic effect of the α-Syn peptide-mediated autoimmune response. The immunization of mice with α-Syn peptides resulted in enhanced autoimmune responses, such as the peptide recall response, polarization toward Th1/Th17 cells, and regulatory T cell imbalance. Furthermore, the α-Syn autoimmune response led to the death of primary neurons cocultured with splenocytes. Treatment with conditioned media from α-Syn peptide-immunized splenocytes induced microglia and toxic A1-type astrocyte activation. Taken together, our results provide evidence of the potential role of the α-Syn-initiated autoimmune response and its contribution to neuronal cell death and glial cell activation.