scholarly journals Comparative Transcriptome Analysis in Monocyte-Derived Macrophages of Asymptomatic GBA Mutation Carriers and Patients with GBA-Associated Parkinson’s Disease

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1545
Author(s):  
Tatiana Usenko ◽  
Anastasia Bezrukova ◽  
Katerina Basharova ◽  
Alexandra Panteleeva ◽  
Mikhail Nikolaev ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcriptome Analysis ◽  
Age At Onset ◽  
Zinc Metabolism ◽  
Comparative Transcriptome ◽  
Comparative Transcriptome Analysis ◽  
Mutation Carriers ◽  
Gba Gene ◽  
Gba Mutations

Mutations of the GBA gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are the greatest genetic risk factor for Parkinson’s disease (PD) with frequency between 5% and 20% across the world. N370S and L444P are the two most common mutations in the GBA gene. PD carriers of severe mutation L444P in the GBA gene is characterized by the earlier age at onset compared to N370S. Not every carrier of GBA mutations develop PD during one’s lifetime. In the current study we aimed to find common gene expression signatures in PD associated with mutation in the GBA gene (GBA-PD) using RNA-seq. We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested.

Biomarkers of Parkinson’s disease in carriers of mutations in the glucocerebrosidase gene

2020 ◽  
pp. 87-89
Author(s):  
С.Н. Пчелина ◽  
М.А. Николаев ◽  
А.Э. Копытова ◽  
Г.В. Байдакова ◽  
К.А. Сенкевич ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gaucher Disease ◽  
Control Group ◽  
Macrophage Culture ◽  
Primary Macrophage ◽  
Mutation Carriers ◽  
Glucocerebrosidase Gene ◽  
Gba Gene ◽  
Gba Mutations

Оценка гексозилсфингозина (HexSph), в крови в настоящее время является чувствительным диагностическим тестом развития болезни Гоше. Мы предположили, что оценка данного метаболита может быть эффективна при выявлении развития болезни Паркинсона (БП) у носителей мутаций в гене GBA (GBA-БП). Концентрация HexSph и ферментативная активность GBA была оценена у пациентов с GBA-БП, бессимптомных носителей мутации в гене GBA, пациентов со спорадической БП (сБП) и в контрольной группе в крови, а также в первичной культуре культивируемых макрофагов. Показано, что оценка уровня HexSph в первичной культуре макрофагов позволяет отличить заболевших БП носителей мутаций в гене GBA, от бессимптомных носителей мутаций и может быть рассмотрена как биомаркер развития БП у носителей мутаций в гене GBA. Assessment of hexosylsphingosine (HexSph) in the blood is currently a sensitive diagnostic test for Gaucher disease. We suggested that the assessment of this metabolite may be effective in detecting the development of Parkinson’s disease (PD) in mutation carriers in the GBA gene (GBA-PD). In the present study HexSph concentration and GBA enzymatic activity were evaluated in patients with GBA-BP, asymptomatic carriers of GBA mutations, patients with sporadic PD (sPD) and the control group in blood, as well as in the primary culture of macrophages. An assessment of HexSph level in the primary macrophage culture makes it possible to distinguish GBA mutation carriers with PD from asymptomatic mutation carriers, and though could be considered as a biomarker of PD development in carriers of GBA mutations.

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.

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