scholarly journals Transcriptome deregulation of peripheral monocytes in GBA-related Parkinson's disease

2021 ◽  
Author(s):  
Giulietta Maria Riboldi ◽  
Ricardo A Vialle ◽  
Elisa Navarro ◽  
Evan Udine ◽  
Katia de Paiva Lopes ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Membrane Trafficking ◽  
Whole Blood ◽  
Differential Expression Analysis ◽  
Enrichment Analysis ◽  
Alpha Synuclein ◽  
Ultrastructural Characterization ◽  
Gba Gene

Background: Genetic mutations in the beta-glucocerebrosidase (GCase), GBA gene, represent the major genetic risk factor for Parkinson's disease (PD). The function of the GBA gene is at the crossroads between the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated. Methods: we characterized the transcriptomic profiles of circulating monocytes and whole blood in a population of patients with PD and healthy controls (CTRL) with (PD/GBA and CTRL/GBA) and without GBA variants (iPD and CTRL) (monocytes: n = 56 iPD, 66 CTRL, 23 PD/GBA, 13 CTRL/GBA; whole blood: n = 616 iPD, 362 CTRLs, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathways enrichment analysis, and outliers detections were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy. Results: We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, GBA-PD showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing (i.e. SNCA, LMNA). Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to nonmanifesting GBA-carriers, as also observed at the ultrastructural levels. Conclusions: Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.

scholarly journals Single Molecule FRET Characterization of Oligomers from Alpha-Synuclein Early Onset Parkinson's Disease Mutants

2014 ◽  
Vol 106 (2) ◽  
pp. 269a ◽  
Author(s):  
Laura Tosatto ◽  
Mathew H. Horrocks ◽  
Cremades Nunilo ◽  
Tim Guilliams ◽  
Mauro Dalla Serra ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Molecule ◽  
Early Onset ◽  
Alpha Synuclein ◽  
Single Molecule Fret ◽  
Early Onset Parkinson’S Disease

scholarly journals Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 105 ◽  
Author(s):  
Maria Zella ◽  
Judith Metzdorf ◽  
Friederike Ostendorf ◽  
Fabian Maass ◽  
Siegfried Muhlack ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Glial Cell ◽  
Dopaminergic Neurons ◽  
Basic Research ◽  
Alpha Synuclein ◽  
Models Of Disease ◽  
Novel Therapeutic Strategies ◽  
Lymphocyte Populations

The etiology of Parkinson’s disease (PD) is significantly influenced by disease-causing changes in the protein alpha-Synuclein (aSyn). It can trigger and promote intracellular stress and thereby impair the function of dopaminergic neurons. However, these damage mechanisms do not only extend to neuronal cells, but also affect most glial cell populations, such as astroglia and microglia, but also T lymphocytes, which can no longer maintain the homeostatic CNS milieu because they produce neuroinflammatory responses to aSyn pathology. Through precise neuropathological examination, molecular characterization of biomaterials, and the use of PET technology, it has been clearly demonstrated that neuroinflammation is involved in human PD. In this review, we provide an in-depth overview of the pathomechanisms that aSyn elicits in models of disease and focus on the affected glial cell and lymphocyte populations and their interaction with pathogenic aSyn species. The interplay between aSyn and glial cells is analyzed both in the basic research setting and in the context of human neuropathology. Ultimately, a strong rationale builds up to therapeutically reduce the burden of pathological aSyn in the CNS. The current antibody-based approaches to lower the amount of aSyn and thereby alleviate neuroinflammatory responses is finally discussed as novel therapeutic strategies for PD.

scholarly journals Non-invasive diagnostic tool for Parkinson’s disease by sebum RNA profile with machine learning

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuya Uehara ◽  
Shin-Ichi Ueno ◽  
Haruka Amano-Takeshige ◽  
Shuji Suzuki ◽  
Yoko Imamichi ◽  
...  
Keyword(s):  
Machine Learning ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Differentially Expressed Genes ◽  
Expression Profiles ◽  
Differential Expression Analysis ◽  
Alpha Synuclein ◽  
Differentially Expressed ◽  
Healthy Controls ◽  
Non Invasive

AbstractParkinson's disease (PD) is a progressive neurodegenerative disease presenting with motor and non-motor symptoms, including skin disorders (seborrheic dermatitis, bullous pemphigoid, and rosacea), skin pathological changes (decreased nerve endings and alpha-synuclein deposition), and metabolic changes of sebum. Recently, a transcriptome method using RNA in skin surface lipids (SSL-RNAs) which can be obtained non-invasively with an oil-blotting film was reported as a novel analytic method of sebum. Here we report transcriptome analyses using SSL-RNAs and the potential of these expression profiles with machine learning as diagnostic biomarkers for PD in double cohorts (PD [n = 15, 50], controls [n = 15, 50]). Differential expression analysis between the patients with PD and healthy controls identified more than 100 differentially expressed genes in the two cohorts. In each cohort, several genes related to oxidative phosphorylation were upregulated, and gene ontology analysis using differentially expressed genes revealed functional processes associated with PD. Furthermore, machine learning using the expression information obtained from the SSL-RNAs was able to efficiently discriminate patients with PD from healthy controls, with an area under the receiver operating characteristic curve of 0.806. This non-invasive gene expression profile of SSL-RNAs may contribute to early PD diagnosis based on the neurodegeneration background.

A Characterization of Misfolded Alpha‐Synuclein in Parkinson’s Disease

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Daniel Shannon ◽  
John-Paul Bugada ◽  
Ethan Collins ◽  
Ellie Fischer ◽  
Delaney Hellard ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein

scholarly journals GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2215
Author(s):  
Silvia Cerri ◽  
Cristina Ghezzi ◽  
Gerardo Ongari ◽  
Stefania Croce ◽  
Micol Avenali ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Fibroblast Cell ◽  
Alpha Synuclein ◽  
Gene Encoding ◽  
Gba Gene ◽  
The Impact ◽  
Gba Mutations

Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson’s disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are not yet fully elucidated. Extracellular vesicles (EVs) have gained increasing importance in neurodegenerative diseases since they can vehiculate pathological molecules potentially promoting disease propagation. Accumulating evidence showed that perturbations of the endosomal–lysosomal pathway can affect EV release and composition. Here, we investigate the impact of GCase deficiency on EV release and their effect in recipient cells. EVs were purified by ultracentrifugation from the supernatant of fibroblast cell lines derived from PD patients with or without GBA mutations and quantified by nanoparticle tracking analysis. SH-SY5Y cells over-expressing alpha-synuclein (α-syn) were used to assess the ability of patient-derived small EVs to affect α-syn expression. We observed that defective GCase activity promotes the release of EVs, independently of mutation severity. Moreover, small EVs released from PD fibroblasts carrying severe mutations increased the intra-cellular levels of phosphorylated α-syn. In summary, our work shows that the dysregulation of small EV trafficking and alpha-synuclein mishandling may play a role in GBA-associated PD.

scholarly journals Therapeutic potential of methylxanthine drug on alpha synuclein protein in Parkinson's disease

2021 ◽  
Author(s):  
Nishant Kumar Rana ◽  
Neha Srivastava ◽  
Bhupendra Kumar ◽  
Abhishek Pathak ◽  
Vijay Nath Mishra
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Enrichment Analysis ◽  
Alpha Synuclein ◽  
Target Protein ◽  
Functional Enrichment ◽  
Glutamate Excitotoxicity ◽  
In Silico Docking

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer. It exists in sporadic (90 to 95%) and familial (5 to 10%) form. Its pathogenesis is due to oxidative stress, glutamate excitotoxicity, protein aggregation, neuroinflammation and neurodegeneration. There is currently no cure for this disease. The protein- protein interaction and gene ontology/functional enrichment analysis have been performed to find out the prominent interactor protein and shared common biological pathways, especially PD pathway. Further in silico docking analysis was performed on target protein to investigate the prominent drug molecule for PD. Through computational molecular virtual screening of small molecules from selected twelve natural compounds, and among these compounds methylxanthine was shown to be prominent inhibitor to SNCA protein that ultimately prevent PD. The interaction of methylxanthine compound with the target protein SNCA suggested that, it interacted with prominent binding site with good docking score and might be involved in blocking the binding of neuroinducing substances like: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to SNCA protein. Thus methylxanthine compounds can be explored as promising drugs for the prevention of Parkinson's disease.

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