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Microglial hyperactivation of the NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome contributes to the pathogenesis of Parkinson's disease (PD). Recently, neuronally expressed NLRP3 was demonstrated to be a Parkin polyubiquitination substrate and a driver of neurodegeneration in PD. However, the role of Parkin in NLRP3 inflammasome activation in microglia remains unclear. Thus, we aimed to investigate whether Parkin regulates NLRP3 in microglia. We investigated the role of Parkin in NLRP3 inflammasome activation through the overexpression of Parkin in BV2 microglial cells and knockout of Parkin in primary microglia after lipopolysaccharide (LPS) treatment. Immunoprecipitation experiments were conducted to quantify the ubiquitination levels of NLRP3 under various conditions and to assess the interaction between Parkin and NLRP3. In vivo experiments were conducted by administering intraperitoneal injections of LPS in wild‐type and Parkin knockout mice. The Rotarod test, pole test, and open field test were performed to evaluate motor functions. Immunofluorescence was performed for pathological detection of key proteins. Overexpression of Parkin mediated NLRP3 degradation via K48‐linked polyubiquitination in microglia. The loss of Parkin activity in LPS‐induced mice resulted in excessive microglial NLRP3 inflammasome assembly, facilitating motor impairment, and dopaminergic neuron loss in the substantia nigra. Accelerating Parkin‐induced NLRP3 degradation by administration of a heat shock protein (HSP90) inhibitor reduced the inflammatory response. Parkin regulates microglial NLRP3 inflammasome activation through polyubiquitination and alleviates neurodegeneration in PD. These results suggest that targeting Parkin‐mediated microglial NLRP3 inflammasome activity could be a potential therapeutic strategy for PD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD), with either rapid eye movement sleep behavior disorder (RBD) or olfactory dysfunction (OD), has been associated with disease progression. However, there is currently heterogeneity in predicting prognosis. Objectives: To identify whether the concurrent presence of OD and probable RBD (pRBD) in PD (Dual hit in PD, PD‐DH) is associated with disease progression. Methods: We included 420 patients with de novo PD from the Parkinson's Progression Markers Initiative: 180 PD only (PD), 82 PD with OD (PD‐OD), 94 PD with pRBD (PD‐pRBD), and 64 PD with both OD and pRBD (PD‐DH). Participants underwent motor and nonmotor evaluations, dopamine transporter imaging, and cerebrospinal fluid (CSF) assessment. Data were analyzed with generalized estimating equations and Cox proportional hazards analysis. Results: The PD‐DH subtype was associated with higher scores and faster progression rates in Movement Disorder Society–Unified PD Rating Scale (MDS‐UPDRS) Parts II and III. Also, patients in PD‐DH group had faster deterioration in nonmotor symptoms, including MDS‐UPDRS Part I score, Montreal Cognitive Assessment, Hopkins Verbal Learning Test–Revised, Wechsler Memory Scale‐Third edition (WMS‐III) Letter Number Sequencing score, Symbol Digit Modalities Test, and Scales for Outcomes in PD–Autonomic scores, with all P values <0.002. Moreover, the PD‐DH subtype had a higher mild cognitive impairment risk (hazard ratio = 1.756, 95% confidence interval [CI] = 1.132–2.722; P = 0.012), faster decline in caudate standard uptake values (β = −0.03, 95% CI = −0.06 to −0.008, P = 0.012), and CSF α‐synuclein levels (β = −77, 95% CI = −149 to −5, P = 0.034) than the PD group. Conclusion: Coexisting pRBD and OD in patients with PD may be associated with faster progressions in motor measurements and in cognitive and autonomic symptoms, indicating PD‐DH as a more aggressive subtype for PD. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence indicates that the apolipoprotein E (APOE) ε4 exacerbates α‐synuclein pathology. Objective: To determine whether APOE ε4 contributes to motor progression in early Parkinson's disease (PD). Methods: Longitudinal data were obtained from 384 patients with PD divided into APOE ε4 carriers (n = 85) and noncarriers (n = 299) in the Parkinson's Progression Marker Initiative. Participants underwent yearly motor assessments over a mean follow‐up period of 78.9 months. Repeated measures and linear mixed models were used to test the effects of APOE ε4. Results: The motor progression was significantly more rapid in patients with PD carrying APOE ε4 than in noncarriers (β = 0.283, P = 0.026, 95% confidence interval: 0.033–0.532). Through subgroup analysis, we found that the effect of APOE ε4 was significant only in patients with high amyloid β burden (β = 0.761, P < 0.001, 95% confidence interval: 0.0356–1.167). Conclusions: APOE ε4 may be associated with rapid motor progression in PD. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Targeted sequencing of Parkinson's disease loci genes s SYT11, FGF20 and other associations. Taken together, our results indicated that the 10 variants in I SYT11 i , I FGF20 i , I GCH1 i genes may not be causative variants for PD in eastern China. One nonsynonymous variant (position: 55312562; c.C552T, p.R186C) in the I GCH1 i gene was found in eight PD patients and four healthy controls (Table 1). [Extracted from the article]