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[Display omitted] • Morphological abnormalities of RBCs were observed in PD patients. • Increased aggregated α-syn in RBC membrane were observed in PD patients. • A decreased proportion of normal RBCs and increased aggregated α-syn in RBC membrane were also observed in PD model mice. • Treating RBCs derived from SNCA knockout mice with aggregated α-syn resulted in a higher percentage of acanthocytes. • Applying aggregated α-syn to RBC membrane directly induced extracellular calcium influx along with morphological changes. Morphological abnormalities of erythrocytes/red blood cells (RBCs), e.g., increased acanthocytes, in Parkinson's disease (PD) have been reported previously, although the underlying mechanisms remain to be characterized. In this study, the potential roles of α-synuclein (α-syn), a protein critically involved in PD and highly abundant in RBCs, were studied in PD patients as well as in a PD mouse model. Transgenic [PAC-Tg (SNCAA53T), A53T] mice overexpressing A53T mutant α-syn and SNCA knockout mice were employed to characterize the effect of α-syn on RBC morphology. In addition to A53T and SNCA knockout mice, the morphology of RBCs of PD patients was also examined using scanning electron microscopy. The potential roles of α-syn were further investigated in cultured RBCs and mice. Morphological abnormalities of RBCs and increased accumulation of aggregated α-syn on the RBC membrane were observed in PD patients. A similar phenomenon was also observed in A53T mice. Furthermore, while mice lacking α-syn expression showed a lower proportion of acanthocytes, treating RBCs derived from SNCA knockout mice with aggregated α-syn resulted in a higher percentage of acanthocytes. In a follow-up proteomic investigation, several major classes of proteins were identified as α-syn-associated proteins on the RBC membrane, seven of which were calcium-binding proteins. Applying aggregated α-syn to the RBC membrane directly induced extracellular calcium influx along with morphological changes; both observations were adequately reversed by blocking calcium influx. This study demonstrated that α-syn plays a critical role in PD-associated morphological abnormalities of RBCs, at least partially via a process mediated by extracellular calcium influx. [ABSTRACT FROM AUTHOR]

IntroductionAlzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood.MethodsTau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects.ResultsThe efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau.ConclusionsTau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD.

Recently, α-synuclein (α-syn) and DJ-1, 2 proteins critically involved in Parkinson's disease (PD), have been shown to be present in saliva, suggesting their potential utility as biomarkers of PD. However, the origin and influence of demographic characteristics (e.g., age or sex) on these proteins are unknown. We identified cheek epithelium, which forms the majority of the cellular component of saliva and is readily accessible clinically, as 1 of several potential sources of salivary α-syn and DJ-1. However, no PD-related trend in the cellular component was present. In the supernatant collected from 198 healthy subjects, no correlation was seen between salivary DJ-1 or α-syn with age. When male and female subjects were analyzed separately, a weak age-dependent increase in DJ-1 level was present in male subjects, along with slightly increased α-syn in female subjects. These results, albeit largely negative, provide critical information for understanding the salivary gland pathology and saliva as a PD biomarker source, and must be considered in future investigations of salivary changes in PD.

Rationale: Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α‐synuclein (α‐syn) in the brain. There is a significant clinical unmet need for disease‐modifying treatments for synucleinopathies. Recently, a seaweed‐derived mixture of oligosaccharides sodium oligomannate, GV‐971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV‐971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms. Methods: α‐Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp‐SNCAA53T mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV‐971 in ameliorating α‐syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp‐SNCAA53T mice 4 weeks after intragastric administration of GV‐971 (200 mg day−1 kg−1). Results: GV‐971 effectively prevented α‐syn aggregation and even disassembled pre‐aggregated α‐syn fibrils, in vitro and ex vivo. In addition, GV‐971 was able to rescue α‐syn‐induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp‐SNCAA53T mouse model, when treated at the age of 5 months, GV‐971 significantly decreased α‐syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions. Conclusions: Our results indicate that GV‐971, when administered at a relatively early stage of the disease process, significantly reduced α‐syn accumulation and aggregation in Prnp‐SNCAA53T mice. Furthermore, GV‐971 corrected α‐syn‐induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV‐971 as a promising disease‐modifying therapy for PD and other synucleinopathies. [ABSTRACT FROM AUTHOR]

Transportation of key proteins via extracellular vesicles has been recently implicated in various neurodegenerative disorders, including Parkinson's disease, as a new mechanism of disease spreading and a new source of biomarkers. Extracellular vesicles likely to be derived from the brain can be isolated from peripheral blood and have been reported to contain higher levels of α-synuclein (α-syn) in Parkinson's disease patients. However, very little is known about extracellular vesicles in multiple system atrophy, a disease that, like Parkinson's disease, involves pathological α-syn aggregation, though the process is centred around oligodendrocytes in multiple system atrophy. In this study, a novel immunocapture technology was developed to isolate blood CNPase-positive, oligodendrocyte-derived enriched microvesicles (OEMVs), followed by fluorescent nanoparticle tracking analysis and assessment of α-syn levels contained within the OEMVs. The results demonstrated that the concentrations of OEMVs were significantly lower in multiple system atrophy patients, compared to Parkinson's disease patients and healthy control subjects. It is also noted that the population of OEMVs involved was mainly in the size range closer to that of exosomes, and that the average α-syn concentrations (per vesicle) contained in these OEMVs were not significantly different among the three groups. The phenomenon of reduced OEMVs was again observed in a transgenic mouse model of multiple system atrophy and in primary oligodendrocyte cultures, and the mechanism involved was likely related, at least in part, to an α-syn-mediated interference in the interaction between syntaxin 4 and VAMP2, leading to the dysfunction of the SNARE complex. These results suggest that reduced OEMVs could be an important mechanism related to pathological α-syn aggregation in oligodendrocytes, and the OEMVs found in peripheral blood could be further explored for their potential as multiple system atrophy biomarkers. [ABSTRACT FROM AUTHOR]

Abstract: Accurate early diagnosis of Parkinson's disease is essential. Using data available from the Parkinson's Progression Markers Initiative study, we identified a multivariate logistic regression model including cerebrospinal fluid α‐synuclein, olfactory function, age, and gender that achieved a high degree of discrimination between patients with Parkinson's disease and healthy control or scan without evidence of dopaminergic deficit participants. Additionally, the model could predict the conversion of scan without evidence of dopaminergic deficit to Parkinson's disease, as well as discriminate between normal and impaired subjects with leucine‐rich repeat kinase 2 mutations. Although further validation is needed, this model may serve as an alternative method to neuroimaging screening in Parkinson's disease studies. [ABSTRACT FROM AUTHOR]

Monomeric α-synuclein (αSN) species are abundant in nerve terminals where they are hypothesized to play a physiological role related to synaptic vesicle turn-over. In Parkinson’s disease (PD) and dementia with Lewy body (DLB), αSN accumulates as aggregated soluble oligomers in terminals, axons and the somatodendritic compartment and insoluble filaments in Lewy inclusions and Lewy neurites. The autosomal dominant heritability associated to mutations in the αSN gene suggest a gain of function associated to aggregated αSN. We have conducted a proteomic screen to identify the αSN interactome in brain synaptosomes. Porcine brain synaptosomes were fractionated, solubilized in non-denaturing detergent and subjected to co-immunoprecipitation using purified recombinant human αSN monomers or oligomers as bait. The isolated αSN binding proteins were identified with LC-LTQ-orbitrap tandem mass spectrometry and quantified by peak area using Windows client application, Skyline Targeted Proteomic Environment. Data are available via ProteomeXchange with identifier PXD001462. To quantify the preferential binding an average fold increase was calculated by comparing binding to monomer and oligomer. We identified 10 proteins preferentially binding monomer, and 76 binding preferentially to oligomer and a group of 92 proteins not displaying any preferred conformation of αSN. The proteomic data were validated by immunoprecipitation in both human and porcine brain extracts using antibodies against monomer αSN interactors: Abl interactor 1, and myelin proteolipid protein, and oligomer interactors: glutamate decarboxylase 2, synapsin 1, glial fibrillary acidic protein, and VAMP-2. We demonstrate the existence of αSN conformation selective ligands and present lists of proteins, whose identity and functions will be useful for modeling normal and pathological αSN dependent processes. [ABSTRACT FROM AUTHOR]