scholarly journals MicroRNAs from extracellular vesicles as a signature for Parkinson's disease

2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Lucas Caldi Gomes ◽  
Anna‐Elisa Roser ◽  
Gaurav Jain ◽  
Tonatiuh Pena Centeno ◽  
Fabian Maass ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Extracellular Vesicles

scholarly journals Protein Binding Partners of Dysregulated miRNAs in Parkinson’s Disease Serum

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 791
Author(s):  
Wolfgang P. Ruf ◽  
Axel Freischmidt ◽  
Veselin Grozdanov ◽  
Valerie Roth ◽  
Sarah J. Brockmann ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Binding ◽  
Neurodegenerative Diseases ◽  
Extracellular Vesicles ◽  
Abundance Pattern ◽  
Binding Partners ◽  
Direct Binding ◽  
Unsupervised Approach ◽  
High Degree

Accumulating evidence suggests that microRNAs (miRNAs) are a contributing factor to neurodegenerative diseases. Although altered miRNA profiles in serum or plasma have been reported for several neurodegenerative diseases, little is known about the interaction between dysregulated miRNAs and their protein binding partners. We found significant alterations of the miRNA abundance pattern in serum and in isolated serum-derived extracellular vesicles of Parkinson’s disease (PD) patients. The differential expression of miRNA in PD patients was more robust in serum than in isolated extracellular vesicles and could separate PD patients from healthy controls in an unsupervised approach to a high degree. We identified a novel protein interaction partner for the strongly dysregulated hsa-mir-4745-5p. Our study provides further evidence for the involvement of miRNAs and HNF4a in PD. The demonstration that miRNA-protein binding might mediate the pathologic effects of HNF4a both by direct binding to it and by binding to proteins regulated by it suggests a complex role for miRNAs in pathology beyond the dysregulation of transcription.

scholarly journals Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson’s Disease

2021 ◽  
Author(s):  
Loredana Leggio ◽  
Francesca L’Episcopo ◽  
Andrea Magrì ◽  
María José Ulloa-Navas ◽  
Greta Paternò ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Extracellular Vesicles ◽  
Caspase 3 ◽  
Cell Communication ◽  
Mitochondrial Complex ◽  
Neuron Death ◽  
Atp Production ◽  
Daergic Neuron ◽  
Clinical Models

AbstractExtracellular vesicles (EVs) are emerging as powerful players in cell-to-cell communication both in health and diseased brain. In Parkinson’s disease (PD) – characterized by selective dopaminergic (DAergic) neuron death in ventral midbrain (VMB) and degeneration of DAergic terminals in striatum (STR) – astrocytes (AS) exert dual harmful/protective functions. When activated by chemokine CCL3, AS promote a robust DAergic neuroprotection both in cellular and pre-clinical models of PD, with mechanisms not fully elucidated. Here we used a combination of techniques to characterize AS-EVs derived from VMB and STR, and investigated their potential to exert neuroprotection. First, we show that: (i) AS of both regions secrete small EVs of ~100 nm; (ii) VMB-AS release more EVs per cell than STR-AS under basal conditions; and (iii) only VMB-AS respond to CCL3 by producing more EVs, suggesting differential AS-EV secretion rate according to PD brain region. Next, addressing AS-EV potential against oxidative stress and mitochondrial toxicity, we found that AS-EVs, especially CCL3-AS-EVs, fully counteract H2O2-induced caspase-3 activation. Furthermore, using high resolution respirometry, we demonstrated that AS-EVs rescue the neuronal mitochondrial complex I function impaired by MPP+, with VMB-AS-EVs fully restoring ATP production in MPP+-injured neurons, highlighting a regional diversity of AS-EVs with neuroprotective implications for PD.

scholarly journals Altered Insulin Receptor Substrate 1 Phosphorylation in Blood Neuron-Derived Extracellular Vesicles From Patients With Parkinson’s Disease

2020 ◽  
Vol 8 ◽  
Author(s):  
Szu-Yi Chou ◽  
Lung Chan ◽  
Chen-Chih Chung ◽  
Jing-Yuan Chiu ◽  
Yi-Chen Hsieh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Extracellular Vesicles ◽  
Insulin Signaling ◽  
Clinical Manifestations ◽  
Insulin Signaling Pathway ◽  
Insulin Receptor Substrate ◽  
Neuronal Markers

IntroductionDiabetes increases the risk of Parkinson’s disease (PD). The phosphorylation of type 1 insulin receptor substrate (IRS-1) determines the function of insulin signaling pathway. Extracellular vesicles (EVs) are emerging as biomarkers of human diseases. The present study investigated whether PD patients exert altered phosphorylation IRS-1 (p-IRS-1) inside the blood neuron-derived extracellular vesicles (NDEVs).Research Design and MethodsIn total, there were 94 patients with PD and 63 healthy controls recruited and their clinical manifestations were evaluated. Blood NDEVs were isolated using the immunoprecipitation method, and Western blot analysis was conducted to assess total IRS-1, p-IRS-1, and downstream substrates level in blood NDEVs. Statistical analysis was performed using SPSS 19.0, and p < 0.05 was considered significant.ResultsThe isolated blood EVs were validated according to the presence of CD63 and HSP70, nanoparticle tracking analysis and transmission electron microscopy. NDEVs were positive with neuronal markers. PD patients exerted significantly higher level of p-IRS-1S312 in blood NDEVs than controls. In addition, the p-IRS-1S312 levels in blood NDEVs was positively associated with the severity of tremor in PD patients after adjusting of age, sex, hemoglobin A1c, and body mass index (BMI).ConclusionPD patients exerted altered p-IRS-1S312 in the blood NDEVs, and also correlated with the severity of tremor. These findings suggested the association between dysfunctional insulin signaling pathway with PD. The role of altered p-IRS-1S312 in blood NDEVs as a segregating biomarker of PD required further cohort study to assess the association with the progression of PD.

scholarly journals Extracellular Vesicles in Alzheimer’s and Parkinson’s Disease: Small Entities with Large Consequences

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2485
Author(s):  
Charysse Vandendriessche ◽  
Arnout Bruggeman ◽  
Caroline Van Cauwenberghe ◽  
Roosmarijn E. Vandenbroucke
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Progression ◽  
Extracellular Vesicles ◽  
Neurodegenerative Disorders ◽  
Neuronal Damage ◽  
Protein Aggregates ◽  
Pathological Changes ◽  
Associated Proteins ◽  
The Brain

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are incurable, devastating neurodegenerative disorders characterized by the formation and spreading of protein aggregates throughout the brain. Although the exact spreading mechanism is not completely understood, extracellular vesicles (EVs) have been proposed as potential contributors. Indeed, EVs have emerged as potential carriers of disease-associated proteins and are therefore thought to play an important role in disease progression, although some beneficial functions have also been attributed to them. EVs can be isolated from a variety of sources, including biofluids, and the analysis of their content can provide a snapshot of ongoing pathological changes in the brain. This underlines their potential as biomarker candidates which is of specific relevance in AD and PD where symptoms only arise after considerable and irreversible neuronal damage has already occurred. In this review, we discuss the known beneficial and detrimental functions of EVs in AD and PD and we highlight their promising potential to be used as biomarkers in both diseases.

scholarly journals Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles

2020 ◽  
Author(s):  
Kathryn A. Jewett ◽  
Ruth E. Thomas ◽  
Chi Q. Phan ◽  
Gillian Milstein ◽  
Selina Yu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Protein Aggregation ◽  
Disease Progression ◽  
Extracellular Vesicles ◽  
Genetic Risk ◽  
Protein Aggregates ◽  
Genetic Risk Factor ◽  
The Brain

AbstractAbnormal protein aggregation within neurons is a key pathologic feature of Parkinson’s disease (PD). The spread of protein aggregates in the brain is associated with clinical disease progression, but how this occurs remains unclear. Mutations in the gene glucosidase, beta acid 1 (GBA), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies, and also associate with faster disease progression. To explore the mechanism by which mutations in GBA influence pathogenesis of these diseases, we previously created a Drosophila model of GBA deficiency (Gba1b) that manifests neurodegeneration, motor and cognitive deficits, and accelerated protein aggregation. Proteomic analysis of Gba1b mutants revealed dysregulation of proteins involved in extracellular vesicle (EV) biology, and we found altered protein composition of EVs from Gba1b mutants. To further investigate this novel mechanism, we hypothesized that GBA may influence the spread of pathogenic protein aggregates throughout the brain via EVs. We found that protein aggregation is reduced cell-autonomously and non-cell-autonomously by expressing wildtype GCase in specific tissues. In particular, accumulation of insoluble ubiquitinated proteins and Ref(2)P in the brains of Gba1b flies are reduced by ectopic expression of GCase in muscle tissue. Neuronal expression of GCase also cell-autonomously rescued protein aggregation in brain as well as non-cell-autonomously rescued protein aggregation in muscle. Muscle-specific GBA expression rescued the elevated levels of EV-intrinsic proteins and Ref(2)P found in EVs from Gba1b flies. Genetically perturbing EV biogenesis in specific tissues in the absence of GCase revealed differential cell-autonomous effects on protein aggregation but could not replicate the non-cell-autonomous rescue observed with tissue-specific GBA expression. Additionally, we identified ectopically expressed GCase within isolated EVs. Together, our findings suggest that GCase deficiency mediates accelerated spread of protein aggregates between cells and tissues via dysregulated EVs, and EV-mediated trafficking of GCase may partially account for the reduction in aggregate spread.Author’s SummaryParkinson’s disease (PD) is a common neurodegenerative disease characterized by abnormal clumps of proteins (aggregates) within the brain and other tissues which can lead to cellular dysfunction and death. Mutations in the gene GBA, which encodes glucocerebrosidase (GCase), are the strongest genetic risk factor for PD, and are associated with faster disease progression. GCase-deficient mutant flies display features suggestive of PD including increased protein aggregation in brain and muscle. We found that restoring GCase protein in the muscle of mutant flies reduced protein aggregation in muscle and the brain, suggesting a mechanism involving interaction between tissues. Previous work indicated that GBA influences extracellular vesicles (EVs) – small membrane-bound structures released by cells to communicate and/or transport cargo from cell to cell. Here, we found increased aggregated proteins within EVs of mutant flies, which was reduced by restoring GCase in muscle. In addition, we found GCase within the EVs, possibly explaining how GCase in one tissue such as muscle could reduce protein aggregation in a distant tissue like the brain. Our findings suggest that GCase influences proteins within EVs, affecting the spread of protein aggregation. This may be important to understanding PD progression and could uncover new targets to slow neurodegeneration.

scholarly journals Glia-Derived Extracellular Vesicles in Parkinson’s Disease

2020 ◽  
Vol 9 (6) ◽  
pp. 1941 ◽  
Author(s):  
Bianca Marchetti ◽  
Loredana Leggio ◽  
Francesca L’Episcopo ◽  
Silvia Vivarelli ◽  
Cataldo Tirolo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Extracellular Vesicles ◽  
Glial Cells ◽  
Donor Cell ◽  
Substantia Nigra Pars Compacta ◽  
Special Focus ◽  
Wide Range ◽  
Messenger Molecules ◽  
New Biomarkers

Glial cells are fundamental players in the central nervous system (CNS) development and homeostasis, both in health and disease states. In Parkinson’s disease (PD), a dysfunctional glia-neuron crosstalk represents a common final pathway contributing to the chronic and progressive death of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc). Notably, glial cells communicating with each other by an array of molecules, can acquire a “beneficial” or “destructive” phenotype, thereby enhancing neuronal death/vulnerability and/or exerting critical neuroprotective and neuroreparative functions, with mechanisms that are actively investigated. An important way of delivering messenger molecules within this glia-neuron cross-talk consists in the secretion of extracellular vesicles (EVs). EVs are nano-sized membranous particles able to convey a wide range of molecular cargoes in a controlled way, depending on the specific donor cell and the microenvironmental milieu. Given the dual role of glia in PD, glia-derived EVs may deliver molecules carrying various messages for the vulnerable/dysfunctional DAergic neurons. Here, we summarize the state-of-the-art of glial-neuron interactions and glia-derived EVs in PD. Also, EVs have the ability to cross the blood brain barrier (BBB), thus acting both within the CNS and outside, in the periphery. In these regards, this review discloses the emerging applications of EVs, with a special focus on glia-derived EVs as potential carriers of new biomarkers and nanotherapeutics for PD.

Extracellular Vesicles as Drug Delivery Vehicles for Potent Redox Enzyme Catalase to Treat Parkinson's Disease

2018 ◽  
Vol 128 ◽  
pp. S18 ◽  
Author(s):  
Matthew J. Haney ◽  
Natalia L. Klyachko ◽  
Yuling Zhao ◽  
Alexander V. Kabanov ◽  
Elena V. Batrakova
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Extracellular Vesicles ◽  
Redox Enzyme ◽  
Drug Delivery Vehicles ◽  
Delivery Vehicles

scholarly journals Portrait of blood-derived extracellular vesicles in patients with Parkinson’s disease

2019 ◽  
Vol 124 ◽  
pp. 163-175 ◽  
Author(s):  
Jérôme Lamontagne-Proulx ◽  
Isabelle St-Amour ◽  
Richard Labib ◽  
Jérémie Pilon ◽  
Hélèna L. Denis ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Extracellular Vesicles
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