Exposure to excessive manganese (Mn) causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson’s disease (IPD). The detailed mechanisms of Mn neurotoxicity in nerve cells, especially in dopaminergic neurons are not yet fully understood. Meanwhile, it is unknown whether there exists a potential antagonist or effective drug for treating neuron damage in manganism. In the present study, we report the discovery of an HIF prolyl-hydroxylase inhibitor, DMOG [N-(2-Methoxy-2-oxoacetyl) glycine methyl ester], that can partially inhibit manganese toxicity not only in the neuroblastoma cell line SH-SY5Y in vitro but also in a mouse model in vivo. A genome-wide methylation DNA analysis was performed using microarray hybridization. Intriguingly, DNA methylation in the promoter region of 226 genes was found to be regulated by MnCl2, while the methylation effects of MnCl2 could be restored with combinatorial DMOG treatment. Furthermore, we found that genes with converted promoter methylation during DMOG antagonism were associated across several categories of molecular function, including mitochondria integrity maintain, cell cycle and DNA damage response and ion transportation. Collectively, our results serve as the basis of a mechanism analysis of neuron damage in manganism and may supply possible gene targets for clinical therapy.

Objective: Anxiety symptoms are prevalent neuropsychiatric manifestations in Parkinson’s disease (PD) and impact the development of motor complications. Our aim was to evaluate the association of GBA variants with the anxiety development in early PD cohort.Methods: This cohort study used data from the Parkinson Progression Marker Initiative. The primary outcome anxiety was assessed by State–Trait Anxiety Inventory (STAI). The association between GBA and longitudinal change in the STAI total score was examined using linear mixed-effects model, and the association between GBA and anxiety progression was examined using Cox survival analysis.Results: A total of 385 patients with PD were included in this study, 39 of them were GBA variant carriers and 346 were idiopathic PD without GBA variants. Patients with GBA variants had faster annual increase in anxiety score (β = 0.44; 95% CI, 0.18 to 0.71; p < 0.001) and were at higher risk of anxiety progression (HR 1.87; 95% CI, 1.03 to 3.41; p = 0.03,). Higher baseline scores for Scales for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT), which indicated the autonomic dysfunction, also independently predicted faster increase in anxiety score (β = 0.48; 95%CI, 0.19 to 0.69; p < 0.001) and higher incidence of anxiety development (HR = 1.05; 95% CI, 1.01 to 1.08; p = 0.008).Interpretation: These findings suggest that longitudinal anxiety symptoms worsening was faster in PD patients who were GBA variant carriers and have dysautonomia, and this association was enhanced if they have both.

Background and Purpose: Rapid eye movement (REM) Rapid eye movement sleep behavior disorder (RBD) is a common non-motor symptom of PD. However, the association between the SNCA rs3910105 genotype and RBD in Parkinson’s disease (PD) remains unclear.Methods: This study used Parkinson’s Progression Markers Initiative (PPMI) data and included 270 patients with newly diagnosed PD without RBD who were divided into SNCA rs3910105 C carriers (CC+CT; n = 187) and TT carriers (n = 83). They were followed up for 5 years to identify the development of RBD. To investigate the influence of cerebrospinal fluid (CSF) alpha-synuclein (α-syn) and β-amyloid 1–42 (Aβ₄₂) in the association between rs3910105 and RBD, the patients were additionally classified into “high-level” and “low-level” groups using cutoff values for CSF α-syn and Aβ₄₂ levels.Results: At baseline, the rs3910105 C allele group had lower CSF α-syn and Aβ₄₂ levels than the TT group. During the 5.0-year follow-up, the rs3910105 C allele group had a higher incidence of RBD than the TT group. In the subgroup analyses, the effect of the rs3910105 C allele was not found in the “low-level” group. However, in the “high-level” group, the rs3910105 C allele independently increased the risk of RBD.Conclusion: The SNCA rs3910105 C allele might be a novel genetic risk factor for RBD development in PD, α-syn pathways might have a role in this association and more basic research would be needed to elucidate the mechanism in the future.

Urine bis(monoacylglycero)phosphate (BMP) levels are reportedly increased in GBA variants carriers of patients with Parkinson’s disease (PD). Freezing of gait (FOG) is a common PD patients, we aimed to evaluate the association of urinary BMP with the risk of FOG development in a large PD cohort. A total of 354 PD patients from the Parkinson’s Progression Markers Initiative (PPMI) were included in this study, and urinary BMPs, including total di-22:6-BMP and 2,2′-di-22:6-BMP, were evaluated at baseline. They were followed up for up to 5 years to examine the progression of FOG. The cumulative incidence of FOG and risk factors for FOG were assessed via Kaplan‒Meier and Cox regression analyses. At baseline, the future FOG group presented higher baseline total di-22:6-BMP levels and 2,2′-di-22:6-BMP levels. During follow-up, baseline urinary 2,2′-di-22:6-BMP was associated with the progression of FOG. In the multivariable Cox analysis, urinary 2,2′-di-22:6-BMP remained an independent predictor of FOG (HR 1.030; 95% CI 1.010–1.051; p = 0.010). In the subgroup analyses, the “high-level” group had a significantly greater incidence of FOG than the “low-level” group and GBA variants independently increased the risk of FOG in the “high-level” group.We found that baseline urinary 2,2′-di-22:6-BMP was a predictor of FOG development in early PD patients.