scholarly journals Transcriptome Analysis of Induced Pluripotent Stem Cells and Neuronal Progenitor Cells, Derived from Discordant Monozygotic Twins with Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3478
Author(s):  
Ivan N. Vlasov ◽  
Anelya Kh. Alieva ◽  
Ekaterina V. Novosadova ◽  
Elena L. Arsenyeva ◽  
Anna V. Rosinskaya ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Factors ◽  
Monozygotic Twins ◽  
Gene Interactions ◽  
Biological Processes ◽  
Neuronal Progenitor ◽  
Downstream Effectors ◽  
Sporadic Cases ◽  
Induced Pluripotent

Parkinson’s Disease (PD) is a widespread severe neurodegenerative disease that is characterized by pronounced deficiency of the dopaminergic system and disruption of the function of other neuromodulator systems. Although heritable genetic factors contribute significantly to PD pathogenesis, only a small percentage of sporadic cases of PD can be explained using known genetic risk factors. Due to that, it could be inferred that changes in gene expression could be important for explaining a significant percentage of PD cases. One of the ways to investigate such changes, while minimizing the effect of genetic factors on experiment, are the study of PD discordant monozygotic twins. In the course of the analysis of transcriptome data obtained from IPSC and NPCs, 20 and 1906 differentially expressed genes were identified respectively. We have observed an overexpression of TNF in NPC cultures, derived from twin with PD. Through investigation of gene interactions and gene involvement in biological processes, we have arrived to a hypothesis that TNF could play a crucial role in PD-related changes occurring in NPC derived from twins with PD, and identified INHBA, WNT7A and DKK1 as possible downstream effectors of TNF.

scholarly journals High Content Screening and Proteomic Analysis Identify the Kinase Inhibitor BX795 as a Potent Neuroprotective Compound in a Patient-Derived Model of Parkinson’s Disease

2020 ◽  
Author(s):  
Nasia Antoniou ◽  
Kanella Prodromidou ◽  
Georgia Kouroupi ◽  
Martina Samiotaki ◽  
George Panayotou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Synthesis ◽  
High Throughput Screening ◽  
Kinase Inhibitor ◽  
Induced Pluripotent Stem Cell ◽  
Neuroprotective Effects ◽  
Mtorc1 Signaling ◽  
Neuroprotective Actions ◽  
Induced Pluripotent

AbstractCombining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease models represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson’s disease bearing the G209A (p.A53T) α-synuclein (αSyn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores disease-associated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the neuroprotective effects of BX795 that comprised a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-αSyn in neuron-like cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have developed an adaptable platform based on p.A53T iPSC-derived neurons for drug screening and identified a promising small molecule with potent neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.

scholarly journals Parkinson's Disease, Genetic Factors and Endoplasmic Reticulum Stress: Systemic Review

2021 ◽  
Vol 10 (3) ◽  
pp. 343-357
Author(s):  
Asunur ADALI ◽  
Selinay Başak - ERDEMLİ-KÖSE ◽  
Anıl YİRÜN ◽  
Pınar ERKEKOĞLU
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Genetic Factors ◽  
Systemic Review

scholarly journals Back to the future: new target-validated Rab antibodies for evaluating LRRK2 signalling in cell biology and Parkinson's disease

2018 ◽  
Vol 475 (1) ◽  
pp. 185-189 ◽  
Author(s):  
Patrick A. Eyers
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Biology ◽  
Human Neutrophils ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Biochemical Journal ◽  
The Future ◽  
Brain Extracts ◽  
Sporadic Cases

The addition of phosphate groups to substrates allows protein kinases to regulate a myriad of biological processes, and contextual analysis of protein-bound phosphate is important for understanding how kinases contribute to physiology and disease. Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase linked to familial and sporadic cases of Parkinson's disease (PD). Recent work established that multiple Rab GTPases are physiological substrates of LRRK2, with Rab10 in particular emerging as a human substrate whose site-specific phosphorylation mirrors hyperactive LRRK2 lesions associated with PD. However, current assays to quantify Rab10 phosphorylation are expensive, time-consuming and technically challenging. In back-to-back studies reported in the Biochemical Journal, Alessi and colleagues teamed up with clinical colleagues and collaborators at the Michael J. Fox Foundation (MJFF) for Parkinson's research to develop, and validate, a panel of exquisitely sensitive phospho-specific Rab antibodies. Of particular interest, the monoclonal antibody-designated MJFF-pRAB10 detects phosphorylated Rab 10 on Thr73 in a variety of cells, brain extracts, PD-derived samples and human neutrophils, the latter representing a previously unrecognised biological resource for LRRK2 signalling analysis. In the future, these antibodies could become universal resources in the fight to understand and quantify connections between LRRK2 and Rab proteins, including those associated with clinical PD.

DNA-methylation analysis of differentially expressed genes in fibroblast cell-lines, derived from monozygotic twins discordant for Parkinson’s disease

2020 ◽  
pp. 73-74
Author(s):  
И.Н. Рыболовлев ◽  
И.Н. Власов ◽  
А.Х. Алиева ◽  
П.А. Сломинский ◽  
М.И. Шадрина
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Cell Lines ◽  
Differentially Expressed Genes ◽  
Regulation Of Gene Expression ◽  
Monozygotic Twins ◽  
Fibroblast Cell ◽  
Differentially Expressed ◽  
Pathogenesis Related

Болезнь Паркинсона (БП) является многофакторным гетерогенным нейродегенеративным заболеванием. Поскольку этиопатогенез БП недостаточно изучен, кроме поиска и анализа изменений на уровне ДНК, необходимо распространить фокус исследований на другие уровни: транскриптом и метилом. Изменения на уровне эпигенома можно исследовать у лиц с идентичной генетической конституцией, такой «моделью» являются дискордантные по этому заболеванию монозиготные близнецы. В исследовании приняло участие 3 пары фенотипически и генотипически монозиготных близнецов русского происхождения; В исследовании приняло участие 3 пары фенотипически и генотипически монозиготных близнецов русского происхождения. БП была уточнена у одного из каждой пары близнецов; длительность течения болезни у близнеца с БП составило по меньшей мере 7 лет.; длительность течения болезни у близнеца с БП составила по меньшей мере 7 лет. Были проанализированы метиломы крови и отобраны точки варьирующегося метилирования. Нами было найдено 8 дифференциально экспрессирующихся генов, которые могут быть дифференциально метилированы. Были выявлены различия между здоровым близнецом и близнецом с БП по уровню метилирования ДНК для ряда этих генов в клеточных линиях фибробластов. Полученные нами данные могут указывать на участие процесса ДНК-метилирования в регуляции транскрипции кандидатных генов-участников патогенеза БП. In recent years it has been convincingly demonstrated that genetic factors play an important role in progression of Parkinson’s disease (PD). Since the etiology of PD has not been elucidated completely yet, it is crucial to shift focus of the research to the broader areas - to dive into investigations of methylome and transcriptome. Epigenetic regulation of gene expression may take part in pathogenesis of PD. Changes in epigenome can be conveniently investigated in case of individuals with almost identical genetic makeup, and monozygotic twins discordant for PD may be such “model”. 3 pairs phenotypically and genotypically monozygous twins of Russian ancestry were enrolled in the study. PD was diagnosed in one of each pair. The disease duration was at least 7 years. Data on blood methylomes was analyzed. Points of variable methylation in blood methylomes were selected. With this approach, 8 differentially expressed genes were found that also may be differentially methylated. Changes in methylation level for some of this genes were found in monozygotic twins discordant for PD fibroblasts cell-lines between healthy and afflicted siblings. Acquired data might suggest participation of DNA-methylation in transcription regulation of PD pathogenesis-related candidate genes.

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