Tourette-like syndrome secondary to Kleefstra syndrome 1 with a de novo microdeletion in the EHMT1 gene.

BACKGROUND: Gills de la Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder manifested by motor and vocal tics. Kleefstra syndrome 1 (KS1), a rare genetic disorder, is caused by haploinsufficiency of the EHMT1 gene and is characterized by intellectual disability (ID), childhood hypotonia, and distinctive facial features. Tourette-like syndrome in KS1 has rarely been reported. CASE PRESENTATION: Here we describe a 7-year-old girl presenting involuntary motor and vocal tics, intellectual disability, childhood hypotonia, and dysmorphic craniofacial appearances, as well as comorbidities including attention deficit-hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and self-injurious behavior (SIB). The patient's CNV-seq testing revealed a de novo 320-kb deletion in the 9q34.3 region encompassing the EHMT1 gene. CONCLUSIONS: This is the first case reporting Tourette-like syndrome secondary to KS1 with a de novo microdeletion in the EHMT1 gene. Our case suggests TS with ID and facial anomalies indicate a genetic cause and broadens the phenotypic and genotypic spectrum of both TS and KS1.

Collaborative plasma biomarkers for Parkinson disease development and progression: A cross-sectional and longitudinal study.

BACKGROUND AND PURPOSE: Relying on a single biomarker for early diagnosis of Parkinson disease (PD) may not yield accurate results. We aimed to assess the combined diagnostic value of multiple biomarkers, including plasma CCL2, plasma CXCL12, and plasma neuronal exosomal α-synuclein (α-syn) for early stage PD diagnosis and their predictive value in PD progression. METHODS: This study included both cross-sectional and longitudinal designs. The CCL2, CXCL12, and neuronal exosomal α-syn levels were analyzed in 50 healthy controls (HCs) and 50 early stage PD patients. Then, a prospective follow-up of 30 early stage PD patients was performed. RESULTS: In early stage PD, we observed a significant increase in CCL2, CXCL12, and plasma neuronal exosomal α-syn compared to HCs (p < 0.05). Utilizing a combined diagnostic approach of CCL2, CXCL12, and α-syn significantly improved the area under the curve (AUC = 0.89, p < 0.001). Spearman correlation analysis revealed that CCL2 levels were correlated with PD clinical stage and autonomic symptoms (p < 0.05). CXCL12 levels were associated with nonmotor symptoms (p < 0.05). Plasma neuronal exosomal α-syn levels were connected to the clinical stage, motor symptoms, and nonmotor symptoms in early stage PD (p < 0.01). In the longitudinal cohort, the Cox regression analysis showed that high CCL2 levels were associated with motor progression after a mean follow-up of 24 months. CONCLUSIONS: Our study suggested that the combined measurement of plasma CCL2, CXCL12, and neuronal exosomal α-syn can improve early stage PD diagnosis, and CCL2 may serve as a prognostic marker for PD progression.

Efficacy of idebenone in the Treatment of iRBD into Synucleinopathies (EITRS): rationale, design, and methodology of a randomized, double-blind, multi-center clinical study.

Background: As the strongest prodromal marker of α-synuclein-specific neurodegeneration, idiopathic REM sleep behavior disorder (iRBD) is becoming a focus of interest in disease-modifying therapy. Idebenone has been widely portrayed as a potent antioxidant targeting mitochondrial dysfunction. Previous study has identified the effect of idebenone on Parkinson's disease with promising outcomes by regulating mitophagy. A novel indication of idebenone should be highlighted in iRBD population. Methods: The EITRS study is a randomized, double-blind, multi-center clinical study assessing the efficacy and safety of idebenone in the treatment of iRBD into synucleinopathies. One hundred forty-two patients (aged 40-75 years old) with clinically diagnosed iRBD are planned to be recruited with 80% statistical power and randomly assigned to idebenone (30 mg each time, three times a day) or matching placebo orally for 5 years. The assessment of rating scales, blood testing and neuroimaging examinations will be conducted at baseline, the 1st, 3rd and 5th year of follow-up. The primary efficacy endpoint is the 5-year conversion rate in patients with iRBD. The secondary endpoint is the safety and tolerability of idebenone in the treatment of iRBD. The study has been launched in July 2020. Discussion: This is the first prospective study designed to identify the efficacy and safety of idebenone on the treatment of iRBD into synucleinopathies. The current results are expected to promote the development of evidence-based recommendations for the management of patients with iRBD. Furthermore, we hope to provide insights on a possible disease-modifying approach with robust evidence. Trial Registration: Clinicaltrials.gov, identifier: NCT04534023.

An oleanolic acid derivative, K73-03, inhibits pancreatic cancer cells proliferation in vitro and in vivo via blocking EGFR/Akt pathway.

Oleanolic acid (OA) and its derivatives show potent anticancer function. Pancreatic cancer (PC) is the fourth core motive of cancer-related deaths worldwide. Epidermal growth factor receptor (EGFR) has been implicated in PC and has been validated as a therapeutic target. Our study demonstrated that K73-03, an OA derivative, was identified as a potent inhibitor of EGFR by using reverse pharmacophore screening and molecular dynamics simulation assays. Moreover, Western blot analysis showed that K73-03 markedly suppressed the levels of phosphorylated-EGFR (p-EGFR) and phosphorylated-Akt (p-Akt). The inhibitory effect of K73-03 on PC cells was assessed in vitro and in vivo. Mechanistically, K73-03 effectively inhibited the cell proliferation of PC cells, and induced apoptosis and autophagy of ASPC-1 cells in a dose-dependent manner. Additionally, pretreatment with chloroquine, an autophagy inhibitor, significantly inhibited K73-03-induced autophagy and enhanced K73-03-induced apoptotic cell death. K73-03 also strongly repressed ASPC-1 cells xenograft growth in vivo. Thus, all these findings provided new clues about OA analog K73-03 as an effective anticancer agent targeted EGFR against ASPC-1 cells, it is worth further evaluation in the future.

Parkinson's disease peripheral immune biomarker profile: a multicentre, cross-sectional and longitudinal study.

BACKGROUND: Inflammations play crucial role in the pathogenesis of Parkinson's disease (PD), however, their possible value in the diagnosis or tracking of the progress of PD is still limited, because of discordant results in the literature and a lack of information regarding its reproducibility. Thus, overall longitudinal and cross-sectional studies are needed. This multicentre study was designed to investigate the association between multiple peripheral immune biomarkers and the development and progression of PD. METHODS: This was a longitudinal and multicentre study. First, we measured the levels of five typical cytokines and five focused chemokines in 76 PD patients and 76 healthy controls (HCs) in a discovery cohort. Then, a validation cohort of 80 PD and 80 HC participants was recruited from four multicentre locations. In addition, a prospective follow-up of early-stage PD patients was performed with significant biomarkers. Finally, we performed further verification in an exploratory set of patients with idiopathic REM sleep behaviour disorder (iRBD). RESULTS: In the discovery set, CXCL12, CX3CL1 and IL-8 levels were significantly higher in PD patients than in HCs (p < 0.05). The receiver-operating characteristic (ROC) curve for a combination of these three biomarkers produced a high area under the curve (AUC) of 0.89 (p < 0.001). Moreover, four biomarkers (the previous three and CCL15) were significantly associated with PD in the discovery and validation cohorts. Furthermore, in the prospective follow-up cohort, CX3CL1 levels were associated with motor progression after a mean interval of 43 months. In addition, CX3CL1 and IL-8 levels were higher in iRBD patients than in HCs. CONCLUSION: We showed a correlation between a profile of four peripheral immune biomarkers and PD development and progression. Our findings may provide a basis whereby PD patients with abnormal inflammatory profiles can be identified and receive timely therapeutic interventions.

Impaired Ocular Tracking and Cortical Atrophy in Idiopathic Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of synucleinopathies. Patients with synucleinopathies frequently display eye movement abnormalities. However, whether patients with iRBD have eye movement abnormalities remains unknown. OBJECTIVE: The aim of this study was to assess eye movement abnormalities and related gray matter alterations and explore whether such abnormalities can serve as biomarkers to indicate phenoconversion to synucleinopathies in iRBD. METHODS: Forty patients with iRBD with early disease progression and 35 healthy control subjects participated in a 15-minute ocular-tracking task that evaluated their control of eye movement abilities. They also underwent clinical assessments for olfactory function, nonmotor symptoms, and autonomic symptoms, all of which are biomarkers to predict phenoconversion to synucleinopathies in iRBD. A subgroup of the participants (20 patients with iRBD and 20 healthy control subjects) also participated in structural magnetic resonance imaging. RESULTS: The ocular-tracking ability in patients with iRBD was inferior to that of healthy control subjects in two aspects: pursuit initiation and steady-state tracking. Cortical thinning in the right visual area V4 in patients with iRBD is coupled with impaired pursuit initiation. Furthermore, prolonged pursuit initiation in patients with iRBD exhibits a trend of correlation with olfactory loss, the earliest biomarker that develops prior to other prodromal biomarkers. CONCLUSIONS: We found ocular-tracking abnormalities in patients with iRBD even early in their disease progression that have not been reported before. These abnormalities are coupled with atrophy of brain areas involved in the perception of object motion and might indicate phenoconversion to synucleinopathies in iRBD. © 2022 International Parkinson and Movement Disorder Society.

Protection of pancreatic ß-cell by phosphocreatine through mitochondrial improvement via the regulation of dual AKT/IRS-1/GSK-3ß and STAT3/Cyp-D signaling pathways.

Diabetes mellitus (DM) is a metabolic syndrome, caused by insufficient insulin secretion or insulin resistance (IR). DM enhances oxidative stress and induces mitochondrial function in different kinds of cell types, including pancreatic ß-cells. Our previous study has showed phosphocreatine (PCr) can advance the mitochondrial function through enhancing the oxidative phosphorylation and electron transport ability in mitochondria damaged by methylglyoxal (MG). Our aim was to explore the potential role of PCr as a molecule to protect mitochondria from diabetes-induced pancreatic ß-cell injury with insulin secretion deficiency or IR through dual AKT/IRS-1/GSK-3ß and STAT3/Cyclophilin D (Cyp-D) signaling pathways. MG-induced INS-1 cell viability, apoptosis, mitochondrial division and fusion, the morphology, and function of mitochondria were suppressed. Flow cytometry was used to detect the production of intracellular reactive oxygen species (ROS) and the changes of intracellular calcium, and the respiratory function was measured by oxygraph-2k. The expressions of AKT, IRS-1, GSK-3ß, STAT3, and Cyp-D were detected using Western blot. The result showed that the oxidative stress-related kinases were significantly restored to the normal level after the pretreatment with PCr. Moreover, PCr pretreatment significantly inhibited cell apoptosis, decreased intracellular calcium, and ROS production, and inhibited mitochondrial division and fusion, and increased ATP synthesis damaged by MG in INS-1 cells. In addition, pretreatment with PCr suppressed Cytochrome C, p-STAT3, and Cyp-D expressions, while increased p-AKT, p-IRS-1, p-GSK-3ß, caspase-3, and caspase-9 expressions. In conclusion, PCr has protective effect on INS-1 cells in vitro and in vivo, relying on AKT mediated STAT3/ Cyp-D pathway to inhibit oxidative stress and restore mitochondrial function, signifying that PCr might become an emerging candidate for the cure of diabetic pancreatic cancer ß-cell damage.

Tandem bispecific antibody prevents pathogenic SHIVSF162P3CN infection and disease progression.

Although progress has been made on constructing potent bi-specific broadly neutralizing antibody (bi-bNAb), few bi-bNAbs have been evaluated against HIV-1/AIDS in non-human primates (NHPs). Here, we report the efficacy of a tandem bi-bNAb, namely BiIA-SG, in Chinese-origin rhesus macaques (CRM) against the CRM-adapted R5-tropic pathogenic SHIVSF162P3CN challenge. Pre-exposure BiIA-SG injection prevents productive viral infection in 6 of 6 CRMs with unmeasurable proviral load, T cell responses, and seroconversion. Single BiIA-SG injection, at day 1 or 3 post viral challenge, significantly reduces peak viremia, achieves undetectable setpoint viremia in 8 of 13 CRMs, and delays disease progression for years in treated CRMs. In contrast, 6 of 8 untreated CRMs develop simian AIDS within 2 years. BiIA-SG-induced long-term protection is associated with CD8+ T cells as determined by anti-CD8ß antibody depletion experiments. Our findings provide a proof-of-concept that bi-bNAb treatment elicits T cell immunity in NHPs, which warrant the clinical development of BiIA-SG for HIV-1 prevention and immunotherapy.

Sustained viremia suppression by SHIVSF162P3CN-recalled effector-memory CD8+ T cells after PD1-based vaccination.

HIV-1 functional cure requires sustained viral suppression without antiretroviral therapy. While effector-memory CD8+ T lymphocytes are essential for viremia control, few vaccines elicit such cellular immunity that could be potently recalled upon viral infection. Here, we investigated a program death-1 (PD1)-based vaccine by fusion of simian immunodeficiency virus capsid antigen to soluble PD1. Homologous vaccinations suppressed setpoint viremia to undetectable levels in vaccinated macaques following a high-dose intravenous challenge by the pathogenic SHIVSF162P3CN. Poly-functional effector-memory CD8+ T cells were not only induced after vaccination, but were also recalled upon viral challenge for viremia control as determined by CD8 depletion. Vaccine-induced effector memory CD8+ subsets displayed high cytotoxicity-related genes by single-cell analysis. Vaccinees with sustained viremia suppression for over two years responded to boost vaccination without viral rebound. These results demonstrated that PD1-based vaccine-induced effector-memory CD8+ T cells were recalled by AIDS virus infection, providing a potential immunotherapy for functional cure.

VPS35 D620N knockin mice recapitulate cardinal features of Parkinson's disease.

D620N mutation in the vacuolar protein sorting 35 ortholog (VPS35) gene causes late-onset, autosomal dominant familial Parkinson's disease (PD) and contributes to idiopathic PD. However, how D620N mutation leads to PD-related deficits in vivo remains unclear. In the present study, we thoroughly characterized the biochemical, pathological, and behavioral changes of a VPS35 D620N knockin (KI) mouse model with chronic aging. We reported that this VPS35 D620N KI model recapitulated a spectrum of cardinal features of PD at 14 months of age which included age-dependent progressive motor deficits, significant changes in the levels of dopamine (DA) and DA metabolites in the striatum, and robust neurodegeneration of the DA neurons in the SNpc and DA terminals in the striatum, accompanied by increased neuroinflammation, and accumulation and aggregation of α-synuclein in DA neurons. Mechanistically, D620N mutation induced mitochondrial fragmentation and dysfunction in aged mice likely through enhanced VPS35-DLP1 interaction and increased turnover of mitochondrial DLP1 complexes in vivo. Finally, the VPS35 D620N KI mice displayed greater susceptibility to MPTP-mediated degeneration of nigrostriatal pathway, indicating that VPS35 D620N mutation increased vulnerability of DA neurons to environmental toxins. Overall, this VPS35 D620N KI mouse model provides a powerful tool for future disease modeling and pharmacological studies of PD. Our data support the involvement of VPS35 in the development of α-synuclein pathology in vivo and revealed the important role of mitochondrial fragmentation/dysfunction in the pathogenesis of VPS35 D620N mutation-associated PD in vivo.

Altered structure and functional connectivity of the central autonomic network in idiopathic rapid eye movement sleep behaviour disorder.

Evidence suggests peripheral autonomic structures may contribute to autonomic dysfunction in idiopathic rapid eye movement sleep behaviour disorder (iRBD). However, whether the central autonomic network (CAN) is affected in iRBD remains unclear. Magnetic resonance imaging data were acquired from 65 participants (32 patients with iRBD and 33 matched healthy controls). We investigated the CAN in patients with iRBD using a combined voxel-based morphometry and resting-state functional connectivity analysis and characterised the relationships between alterations of the CAN and autonomic symptoms. Patients with iRBD had significantly reduced grey matter volume in the brainstem, anterior cingulate and insula compared with healthy controls. Functional connectivity analysis revealed reduced functional connectivity between the brainstem and the cerebellum posterior lobe, temporal lobe and anterior cingulate in patients with iRBD. In patients with iRBD, both reduced grey matter volume and decreased functional connectivity of the CAN were negatively correlated with the Scales for Outcomes in Parkinson's Disease-Autonomic scores. The present study demonstrated that both the structure and the functional connectivity of the CAN were abnormal in patients with iRBD. In addition, correlation analysis suggested that CAN abnormalities may also play a role in the development of autonomic symptoms in iRBD.

The neuroprotective effects of phosphocreatine on Amyloid Beta 25-35-induced differentiated neuronal cell death through inhibition of AKT /GSK-3ß /Tau/APP /CDK5 pathways in vivo and vitro.

Alzheimer (AD) is a degenerative disease that can lead memory loss and behavioral dysfunction. Aß protein and phosphorylation of Tau protein are related to the onset of AD. However, at present, its treatment and drugs are limited. The purpose of our study is to evaluate whether phosphocreatine (PCr) could protect neuronal injury induced by Aß protein in vivo and in vitro through AKT/GSK-3ß/Tau/APP/CDK5 pathways. Differentiated PC-12 cells were cultured with Aß25-35 for 24 h, while the mice were injected with D-Galactose for eight weeks, both of them were pretreated with PCr for 2 h. The results showed PCr could obviously induce cells and hippocampus apoptosis using DAPI and TUNEL. PCr decreased the levels of intercellular reactive oxygen species (ROS) and malondialdehyde (MDA), and increased the activities of superoxide dismutase (SOD). Besides, the apoptosis pathway was detected using Western blot, showing that PCr could significantly reduce caspase-3, caspase-9, Bcl-2/Bax expression in vivo and in vitro. At the same time, PCr could decreased Ca2+ and apoptosis by Flow Cytometry in PC-12 cells. We observed that the morphological alteration of hippocampus injury was mitigated with the pretreatment of PCr. Furthermore, PCr pretreatment could decrease Aß25-35-induced PC-12 cells apoptosis with APP cDNA transfection, which up-regulated AKT/GSK-3ß/CDK5 pathways and induced Tau phosphorylation. In summary, PCr could reduce Aß25-35 toxicity to protect neuronal cells via AKT/GSK-3ß/CDK5 pathways.

P2X4R Overexpression Upregulates Interleukin-6 and Exacerbates 6-OHDA-Induced Dopaminergic Degeneration in a Rat Model of PD.

The pathogenesis of Parkinson's disease (PD) remains elusive. Current thinking suggests that the activation of microglia and the subsequent release of inflammatory factors, including interleukin-6 (IL-6), are involved in the pathogenesis of PD. P2X4 receptor (P2X4R) is a member of the P2X superfamily of ion channels activated by ATP. To study the possible effect of the ATP-P2X4R signal axis on IL-6 in PD, lentivirus carrying the P2X4R-overexpression gene or empty vector was injected into the substantia nigra (SN) of rats, followed by treatment of 6-hydroxydopamine (6-OHDA) or saline 1 week later. The research found the relative expression of P2X4R in the 6-OHDA-induced PD rat models was notably higher than that in the normal. And P2X4R overexpression could upregulate the expression of IL-6, reduce the amount of dopaminergic (DA) neurons in the SN of PD rats, suggesting that P2X4R may mediate the production of IL-6 to damage DA neurons in the SN. Our data revealed the important role of P2X4R in modulating IL-6, which leads to neuroinflammation involved in PD pathogenesis.

miR-421 up-regulation by the oleanolic acid derivative K73-03 regulates epigenetically SPINK1 transcription in pancreatic cancer cells leading to metabolic changes and enhanced apoptosis.

SPINK1 overexpression promotes cancer cell aggressiveness and confers chemo-resistance to multiple drugs in pancreatic cancer. Oleanolic acid (OA) derivatives possess active effects against different cancers. Here we report the effect of K73-03, a new novel OA derivative, against pancreatic cancer through mitochondrial dysfunction via miR-421/SPINK1 regulation. We examined the binding ability of miR-421 with SPINK1-3'UTR Luciferase reporter assays. Moreover, miR-421/SPINK1 expressions in pancreatic cancer, with or without K73-03 treatment, were evaluated. Cells viability, migration, autophagy, mitochondrial function and apoptosis were examined with or without K73-03 treatment. We established that the K73-03 effect on the miR-421 that plays a crucial role in the regulation of SPINK1 in pancreatic cancer. Our findings indicated that K73-03 inhibited the mitochondrial function that led to inducing autophagy and apoptosis through epigenetic SPINK1 down-regulation via miR-421 up-regulation in pancreatic cancer. Furthermore, the inhibition of miR-421 expression in pancreatic cancer cells abolished the efficacy of K73-03 against SPINK1 oncogenic properties. We found an interesting finding that the interaction between miR-421 and SPINK1 is related to mitochondrial function through the effect of K73-03. Further, SPINK1 appear to be the molecular targets of K73-03 especially more than gemcitabine.

Dynamic functional connectivity impairments in idiopathic rapid eye movement sleep behavior disorder.

INTRODUCTION: Previous functional magnetic resonance imaging (fMRI) studies typically analyzed static functional connectivity (sFC) to reveal the pathophysiology of iRBD and overlooked the dynamic nature of brain activity. Thus, we aimed to explore whether iRBD showed abnormalities of brain network dynamics using the dynamic functional connectivity (dFC) approach. METHODS: Resting-state fMRI data from 33 iRBD patients and 38 matched healthy controls were analyzed using an independent component analysis, sliding window correlation and k-means clustering. Relationships between clinical symptoms and abnormal dFC were evaluated using Spearman's correlation analysis. RESULTS: Four distinct connectivity states were identified to characterize and compare dFC patterns. We demonstrated that iRBD had fewer occurrences and a shorter dwell time in the infrequent and strongly connected State 1, but with more occurrences and a longer dwell time in the frequent and sparsely connected State 2. In addition, iRBD patients showed significantly decreased FC in certain dFC states compared to healthy controls. More importantly, the impairments in the temporal properties of State 2 were found to be associated RBDSQ scores in the patient group. CONCLUSIONS: This study detected dFC impairments in iRBD patients and provided new insights into the pathophysiology of iRBD, which might contribute to the development of disease-modifying drugs in future clinical trials.

SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 are associated with Parkinson's disease in southern Chinese population.

Numerous single nucleotide polymorphisms (SNPs), which have been identified as susceptibility factors for Parkinson's disease (PD) as per genome-wide association studies, have not been fully characterized for PD patients in China. This study aimed to replicate the relationship between 12 novel SNPs of 12 genes and PD risk in southern Chinese population. Twelve SNPs of 12 genes were detected in 231 PD patients and 249 controls, using the SNaPshot technique. Meta-analysis was used to assess heterogeneity of effect sizes between this study and published data. The impact of SNPs on gene expression was investigated by analysing the SNP-gene association in the expression quantitative trait loci (eQTL) data sets. rs8180209 of SNCA (allele model: P = .047, OR = 0.77; additive model: P = .047, OR = 0.77), rs2270968 of MCCC1 (dominant model: P = .024, OR = 1.52), rs7479949 of DLG2 (recessive model; P = .019, OR = 1.52), rs10748818 of GBF1 (additive model: P < .001, OR = 0.37), and rs4771268 of MBNL2 (recessive model: P = .003, OR = 0.48) were replicated to be significantly associated with the increased risk of PD. Noteworthy, a meta-analysis of previous studies suggested rs8180209, rs2270968, rs7479949 and rs4771268 were in line with those of our cohort. Our study replicated five novel functional SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 could be associated with increased risk of PD in southern Chinese population.

RAGE Silencing Ameliorates Neuroinflammation by Inhibition of p38-NF-κB Signaling Pathway in Mouse Model of Parkinson's Disease.

Accumulating evidence suggested that neuroinflammation played a crucial role in dopaminergic neuronal death in Parkinson's disease (PD). The receptor for advanced glycation end products (RAGE), a multi-ligand receptor of the immunoglobulin superfamily, has been proposed as a key molecule in the onset and sustainment of the inflammatory response. Engagement of RAGE contributed to neuroinflammation by upregulating nuclear factor-κB (NF-κB) as well as cytokines. The aim of the present study was to investigate the expression of RAGE in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and elucidate the RAGE signal pathway involved in the inflammation. Results showed that RAGE protein and pro-inflammatory cytokines cyclooxygenase type 2 (COX-2) were upregulated in MPTP-treated mice. Further experiments showed that RAGE ablation inhibited phosphorylation of IκB and p38 and protected nigral dopaminergic neurons against cell death in the substantia nigra (SN). These results suggested that RAGE participated in the pathogenesis of PD by neuroinflammation and p38MAPK-NFκB signal pathway may be involved in the process. Moreover, interfering with RAGE signaling pathway may be a reasonable therapeutic option in slowing PD development and progression.

SNCA Hypomethylation in Rapid Eye Movement Sleep Behavior Disorder Is a Potential Biomarker for Parkinson's Disease.

BACKGROUND: α-Synuclein has been related to the pathogenesis of Parkinson's disease (PD), but it has not thoroughly been investigated in idiopathic rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: We aimed to explore whether there were different distributions of α-synuclein at a genetic and/or protein level in patients with iRBD. METHODS: We included 30 patients with iRBD, 30 patients with PD, and 30 age- and sex-matched healthy controls (HCs) in this study. The SNCA methylation and mRNA levels were determined using bisulfite sequencing and quantitative reverse transcription polymerase chain reaction. The plasma levels of exosome α-synuclein were measured using Meso Scale Discovery. RESULTS: SNCA methylation showed different distribution among HC, iRBD and PD groups (HC vs RBD: p = 0.011; HC vs PD: p < 0.001; RBD vs PD: p = 0.027). However, plasma exosomal α-synuclein levels were only elevated in patients with PD compared to those in HCs (p = 0.027), and were associated with the SNCA methylation only in the PD group (p = 0.030, r = -0.397). CONCLUSION: SNCA hypomethylation in leukocytes existed both in patients with iRBD and those with PD, indicating that SNCA methylation could be a potential biomarker for early PD diagnosis.