| 1. |
- Azevedo, Carla, et al.
(författare)
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Generation of an induced pluripotent stem cell line (CSC-32) from a patient with Parkinson's disease carrying a heterozygous variation p.A53T in the SNCA gene
- 2020
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Ingår i: Stem Cell Research. - : Elsevier BV. - 1873-5061. ; 43
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Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the generation of an induced pluripotent stem cell (iPSC) line, from a male patient diagnosed with Parkinson's disease (PD). The patient carries a heterozygous variation p.A53T in the SNCA gene. Skin fibroblasts were reprogrammed using the non-integrating Sendai virus technology to deliver OCT3/4, SOX2, c-MYC and KLF4 factors. The generated iPSC line (CSC-32) preserved the mutation, displayed expression of common pluripotency markers, differentiated into derivatives of the three germ layers, and exhibited a normal karyotype. The clone CSC-32B is presented thereafter; it can be used to study the mechanisms underlying PD pathogenesis.
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| 2. |
- Azevedo, Carla, et al.
(författare)
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Parkinsons disease and multiple system atrophy patient iPSC-derived oligodendrocytes exhibit alpha-synuclein-induced changes in maturation and immune reactive properties
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:12
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Tidskriftsartikel (refereegranskat)abstract
- Limited evidence has shed light on how aSYN proteins affect the oligodendrocyte phenotype and pathogenesis in synucleinopathies that include Parkinsons disease (PD) and multiple system atrophy (MSA). Here, we investigated early transcriptomic changes within PD and MSA O4(+) oligodendrocyte lineage cells (OLCs) generated from patient-induced pluripotent stem cells (iPSCs). We found impaired maturation of PD and MSA O4(+) OLCs compared to controls. This phenotype was associated with changes in the human leukocyte antigen (HLA) genes, the immunoproteasome subunit PSMB9, and the complement component C4b for aSYN p.A53T and MSA O4(+) OLCs, but not in SNCA(trip) O4(+) OLCs despite high levels of aSYN assembly formation. Moreover, SNCA overexpression resulted in the development of O4(+) OLCs, whereas exogenous treatment with aSYN species led to significant toxicity. Notably, transcriptome profiling of genes encoding proteins forming Lewy bodies and glial cytoplasmic inclusions revealed clustering of PD aSYN p.A53T O4(+) OLCs with MSA O4(+) OLCs. Our work identifies early phenotypic and pathogenic changes within human PD and MSA O4(+) OLCs.
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| 3. |
- Djelloul, Mehdi, et al.
(författare)
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Reporting on methods to generate and purify rodent and human oligodendrocytes from different sources
- 2017
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Ingår i: Stem Cell Research. - : Elsevier BV. - 1873-5061. ; 20, s. 58-66
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Tidskriftsartikel (refereegranskat)abstract
- Oligodendrocytes are part of the glial cells located in the central nervous system, capable of providing trophic support to neurons and ensheathing their axons. These cells can become dysfunctional under pathologic condition. Rodent and human pluripotent stem cells are inexhaustible sources for producing oligodendrocytes that can be used for disease modeling and cell replacement therapy studies. They also offer many opportunities to model the contribution of oligodendrocytes in non-genetic disorders such as multiple system atrophy. In this method article, we provide robust and reproducible differentiation protocols to obtain oligodendrocyte progenitor cells and purify them using fluorescence activated cell sorting.
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| 4. |
- Gustavsson, Nadja, et al.
(författare)
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Generation of an induced pluripotent stem cell line (CSC-46) from a patient with Parkinson's disease carrying a novel p.R301C mutation in the GBA gene
- 2019
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Ingår i: Stem Cell Research. - : Elsevier BV. - 1873-5061. ; 34
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the glucocerebrosidase (GBA) gene have been associated with the development of Parkinson's disease (PD). An induced pluripotent stem cell (iPSC) line was generated from a 60-year old patient diagnosed with PD and carrying a new mutation variant p.R301C in GBA. Using non-integrating Sendai virus-based technology, we utilized OCT3/4, SOX2, c-MYC and KLF4 transcription factors to reprogram skin fibroblasts into iPSCs. The generated iPSC line retained the mutation, displayed expression of common pluripotency markers, differentiated into the three germ layers, and exhibited normal karyotype. The iPSC line can be further used for studying PD pathogenesis.
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| 5. |
- Marote, Ana, et al.
(författare)
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Generation of an induced pluripotent stem cell line (CSC-41) from a Parkinson's disease patient carrying a p.G2019S mutation in the LRRK2 gene
- 2018
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Ingår i: Stem Cell Research. - : Elsevier BV. - 1873-5061. ; 28, s. 44-47
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Tidskriftsartikel (refereegranskat)abstract
- The leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation is the most common genetic cause of Parkinson's disease (PD). An induced pluripotent stem cell (iPSC) line CSC-41 was generated from a 75-year old patient diagnosed with PD caused by a p.G2019S mutation in LRRK2. Skin fibroblasts were reprogrammed using a non-integrating Sendai virus-based technology to deliver OCT3/4, SOX2, c-MYC and KLF4 transcription factors. The generated iPSC line exhibits expression of common pluripotency markers, differentiates into the three germ layers and has a normal karyotype. The iPSC line can be used to explore the association between LRRK2 mutation and PD.
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| 6. |
- Marote, Ana, et al.
(författare)
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Generation of an induced pluripotent stem cell line (CSC-44) from a Parkinson's disease patient carrying a compound heterozygous mutation (c.823C > T and EX6 del) in the PARK2 gene
- 2018
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Ingår i: Stem Cell Research. - : Elsevier BV. - 1873-5061. ; 27, s. 90-94
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the PARK2 gene, which encodes PARKIN, are the most frequent cause of autosomal recessive Parkinson's disease (PD). We report the generation of an induced pluripotent stem cell (iPSC) line from a 78-year-old patient carrying a compound heterozygous mutation (c.823C > T and EX6del) in the PARK2 gene. Skin fibroblasts were reprogrammed using the non-integrating Sendai virus technology to deliver OCT3/4, SOX2, c-MYC and KLF4 factors. The generated cell line CSC-44 exhibits expression of common pluripotency markers, in vitro differentiation into the three germ layers and normal karyotype. This iPSC line can be used to explore the association between PARK2 mutations and PD.
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| 7. |
- Marote, Ana, et al.
(författare)
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Generation of an integration-free induced pluripotent stem cell line (CSC-43J) from a patient with sporadic Parkinson's disease
- 2018
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Ingår i: Stem Cell Research. - : Elsevier BV. - 1873-5061. ; 27, s. 82-85
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Tidskriftsartikel (refereegranskat)abstract
- An induced pluripotent stem cell (iPSC) line was generated from a 36-year-old patient with sporadic Parkinson's disease (PD). Skin fibroblasts were reprogrammed using the non-integrating Sendai virus technology to deliver OCT3/4, SOX2, c-MYC and KLF4 factors. The generated cell line (CSC-43) exhibits expression of common pluripotency markers, in vitro differentiation into three germ layers and normal karyotype. This iPSC line can be used to study the mechanisms underlying the development of PD.
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| 8. |
- Pera, Edgar M., et al.
(författare)
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Inhibition of the serine protease HtrA1 by SerpinE2 suggests an extracellular proteolytic pathway in the control of neural crest migration
- 2023
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Ingår i: eLife. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- We previously showed that SerpinE2 and the serine protease HtrA1 modulate fibro-blast growth factor (FGF) signaling in germ layer specification and head-to-tail development of Xenopus embryos. Here, we present an extracellular proteolytic mechanism involving this serpin-protease system in the developing neural crest (NC). Knockdown of SerpinE2 by injected antisense morpholino oligonucleotides did not affect the specification of NC progenitors but instead inhibited the migration of NC cells, causing defects in dorsal fin, melanocyte, and craniofacial cartilage formation. Similarly, overexpression of the HtrA1 protease impaired NC cell migration and the formation of NC-derived structures. The phenotype of SerpinE2 knockdown was overcome by concomitant downregulation of HtrA1, indicating that SerpinE2 stimulates NC migration by inhibiting endog-enous HtrA1 activity. SerpinE2 binds to HtrA1, and the HtrA1 protease triggers degradation of the cell surface proteoglycan Syndecan-4 (Sdc4). Microinjection of Sdc4 mRNA partially rescued NC migration defects induced by both HtrA1 upregulation and SerpinE2 downregulation. These epistatic experiments suggest a proteolytic pathway by a double inhibition mechanism: SerpinE2 ┤HtrA1 protease ┤Syndecan-4 → NC cell migration.
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| 9. |
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| 10. |
- Pomeshchik, Yuriy, et al.
(författare)
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Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction and progression of Alzheimer's disease pathogenesis
- 2023
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Ingår i: Acta Neuropathologica Communications. - 2051-5960. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampus is a primary region affected in Alzheimer's disease (AD). Because AD postmortem brain tissue is not available prior to symptomatic stage, we lack understanding of early cellular pathogenic mechanisms. To address this issue, we examined the cellular origin and progression of AD pathogenesis by comparing patient-based model systems including iPSC-derived brain cells transplanted into the mouse brain hippocampus. Proteomic analysis of the graft enabled the identification of pathways and network dysfunction in AD patient brain cells, associated with increased levels of Aβ-42 and β-sheet structures. Interestingly, the host cells surrounding the AD graft also presented alterations in cellular biological pathways. Furthermore, proteomic analysis across human iPSC-based models and human post-mortem hippocampal tissue projected coherent longitudinal cellular changes indicative of early to end stage AD cellular pathogenesis. Our data showcase patient-based models to study the cell autonomous origin and progression of AD pathogenesis.
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