Generation of induced pluripotent stem cell line RCPCMi004-A derived from patient with Parkinson's disease with deletion of the exon 2 in PARK2 gene

Shuvalova, L.D.; Eremeev, A V; Bogomazova, Alexandra N.; Новосадова, Е. В.; Zerkalenkova, Elena; Olshanskaya, Yu. V.; Fedotova, E. Yu.; Глаголева, Е.С.; Иллариошкин, С. Н.; Lebedeva, Olga; Lagarkova, Maria A.

doi:10.1016/j.scr.2020.101733

Cited by 8 publications

(3 citation statements)

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“…Lastly, the identified proteins obtained from skin fibroblasts of patients may not be the same as those of a patient's neuronal cells, which are more likely to demonstrate a direct clinical correlation with the variants. The results from studies focused on induced dopaminergic neurons derived from pluripotent stem cells from patients should reveal more precisely the molecular defects that occur in those neuronal cells (67,68). Nevertheless, the present study on primary skin fibroblasts of patients with PD with different variants of GBA and PARK2 genes provides unique proteome profiles, which suggest that the proteins identified may serve important roles in the disease status.…”

Section: Discussionmentioning

confidence: 82%

Aberrant proteins expressed in skin fibroblasts of Parkinson's disease patients carrying heterozygous variants of glucocerebrosidase and parkin genes

et al. 2021

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Parkinson's disease (PD) is a neurodegenerative disorder that affects movement, and its development is associated with environmental and genetic factors. Genetic variants in GBA and PARK2 are important risk factors implicated in the development of PD; however, their precise roles have yet to be elucidated. The present study aimed to identify and analyse proteins from the skin fibroblasts of patients with PD carrying heterozygous GBA and PARK2 variants, and from healthy controls. Liquid chromatography coupled with tandem mass spectrometry and label-free quantitative proteomics were performed to identify and compare differential protein expression levels. Moreover, protein-protein interaction networks were assessed using Search Tool for Retrieval of Interacting Genes analysis. Using these proteomic approaches, 122 and 119 differentially expressed proteins from skin fibroblasts of patients with PD carrying heterozygous GBA and PARK2 variants, respectively, were identified and compared. According to the results of protein-protein interaction and Gene Ontology analyses, 14 proteins involved in the negative regulation of macromolecules and mRNA metabolic processes, and protein targeting to the membrane exhibited the largest degree of differential expression in the fibroblasts of patients with PD with a GBA variant, whereas 20 proteins involved in the regulation of biological quality, NAD metabolic process and cytoskeletal organization exhibited the largest degree of differential expression in the fibroblasts of patients with PD with a PARK2 variant. Among these, the expression levels of annexin A2 and tubulin β chain, were most strongly upregulated in the fibroblasts of patients with GBA-PD and PARK2-PD, respectively. Other predominantly expressed proteins were confirmed by western blotting, and the results were consistent with those of the quantitative proteomic analysis. Collectively, the results of the present study demonstrated that the proteomic patterns of fibroblasts of patients with PD carrying heterozygous GBA and PARK2 variants are different and unique. Aberrant expression of the proteins affected by these variants may reflect physiological changes that also occur in neurons, resulting in PD development and progression.

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Section: Discussionmentioning

confidence: 82%

Aberrant proteins expressed in skin fibroblasts of Parkinson's disease patients carrying heterozygous variants of glucocerebrosidase and parkin genes

et al. 2021

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“…After seven days, fibroblasts were passaged with 0.25% Trypsin (Gibco). Human skin fibroblasts from the patient and the healthy donor were reprogrammed using the protocol described in Shuvalolva et al, 2020 (62).…”

Section: Methodsmentioning

confidence: 99%

Cortical neurons obtained from patient-derived iPSCs with GNAO1 p.G203R variant show altered differentiation and functional properties

Benedetti,

D’Andrea,

Colantoni

et al. 2023

Preprint

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Pathogenic variants in the GNAO1 gene, encoding for the α subunit of a heterotrimeric guanine nucleotide-binding protein (Go), have been linked to encephalopathy characterized by different combinations of neurological symptoms, including developmental delay, hypotonia, epilepsy and hyperkinetic movement disorder with life-threatening paroxysmal exacerbations. Currently there are no curative but only symptomatic treatments, and little is known on the pathophysiology of the disease. In this paper we report the characterization of a new in vitro model system based on patient-derived induced pluripotent stem cells (iPSCs) carrying the recurrent p.G203R amino acid substitution in Gαo, and a genetically corrected isogenic control line. Upon induction of differentiation into cortical neurons, patient's cells showed altered expression of neural genes as well as premature and defective differentiation processes. Functional characterization showed lower basal intracellular free calcium concentration ([Ca2+]i), reduced frequency of spontaneous activity, and a smaller response to several neurotransmitters. These results suggest that the GNAO1 pathogenic variant causes a neurodevelopmental phenotype characterized by aberrant differentiation of neural precursor cells leading to a significant alteration of neuronal communication and signal transduction.

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“…Particularly, the generation of neurons and glial cells from a patient became possible, thereby allowing the reconstruction of key processes of brain plasticity, development of brain tissue in vitro models, and establishment of isogenic platforms for cell-replacement therapy and cell transplantation [68]. As we have shown before, such an approach was effective in the generation of PD-derived iPSC lines with different mutations for studying defects in neurotrophic factors signaling affecting neuronal development [19], personalized modeling of PD pathogenesis [69], and screening of drug candidates [70,71]. The optimized protocols for getting dopaminergic differentiated neurons from iPSCs have been suggested [72,73], and they include the recruitment of stem cells with the transforming growth factor-beta (TGFβ) antagonists, activation of Hedgehog, Wnt, and fibroblast growth factor 8 (FGF8) signaling pathways or expression of Lmx1a, Foxa2, and Nurr1 and other midbrain-specific transcription factors for getting the midbrain floor-plate progenitors, followed by the application of neurotrophic factors (brain-derived neurotrophic factor BDNF, glia cell line-derived neurotrophic factor GDNF) and Notch receptor antagonists to induce the terminal differentiation of cells toward a dopaminergic phenotype.…”

Section: Generation Of Ipsc-derived Dopaminergic Neuronsmentioning

confidence: 99%

Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease

Салмина

Kapkaeva

Ветчинова

et al. 2021

IJMS

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Neurogenesis is a key mechanism of brain development and plasticity, which is impaired in chronic neurodegeneration, including Parkinson’s disease. The accumulation of aberrant α-synuclein is one of the features of PD. Being secreted, this protein produces a prominent neurotoxic effect, alters synaptic plasticity, deregulates intercellular communication, and supports the development of neuroinflammation, thereby providing propagation of pathological events leading to the establishment of a PD-specific phenotype. Multidirectional and ambiguous effects of α-synuclein on adult neurogenesis suggest that impaired neurogenesis should be considered as a target for the prevention of cell loss and restoration of neurological functions. Thus, stimulation of endogenous neurogenesis or cell-replacement therapy with stem cell-derived differentiated neurons raises new hopes for the development of effective and safe technologies for treating PD neurodegeneration. Given the rapid development of optogenetics, it is not surprising that this method has already been repeatedly tested in manipulating neurogenesis in vivo and in vitro via targeting stem or progenitor cells. However, niche astrocytes could also serve as promising candidates for controlling neuronal differentiation and improving the functional integration of newly formed neurons within the brain tissue. In this review, we mainly focus on current approaches to assess neurogenesis and prospects in the application of optogenetic protocols to restore the neurogenesis in Parkinson’s disease.

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Generation of induced pluripotent stem cell line RCPCMi004-A derived from patient with Parkinson's disease with deletion of the exon 2 in PARK2 gene

Cited by 8 publications

References 5 publications

Aberrant proteins expressed in skin fibroblasts of Parkinson's disease patients carrying heterozygous variants of glucocerebrosidase and parkin genes

Aberrant proteins expressed in skin fibroblasts of Parkinson's disease patients carrying heterozygous variants of glucocerebrosidase and parkin genes

Cortical neurons obtained from patient-derived iPSCs with GNAO1 p.G203R variant show altered differentiation and functional properties

Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease

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