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See detailSingle-cell transcriptomics of human iPSC differentiation dynamics reveal a core molecular network of Parkinson’s disease
Novak, Gabriela; Kyriakis, Dimitrios UL; Grzyb, Kamil UL et al

in Communications Biology (2022), 5(1), 1--19

Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly ... [more ▼]

Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly understood and there is no treatment to reverse PD progression. Here, we investigated the disease mechanism using mDA neurons differentiated from human induced pluripotent stem cells (hiPSCs) carrying the ILE368ASN mutation within the PINK1 gene, which is strongly associated with PD. Single-cell RNA sequencing (RNAseq) and gene expression analysis of a PINK1-ILE368ASN and a control cell line identified genes differentially expressed during mDA neuron differentiation. Network analysis revealed that these genes form a core network, members of which interact with all known 19 protein-coding Parkinson’s disease-associated genes. This core network encompasses key PD-associated pathways, including ubiquitination, mitochondrial function, protein processing, RNA metabolism, and vesicular transport. Proteomics analysis showed a consistent alteration in proteins of dopamine metabolism, indicating a defect of dopaminergic metabolism in PINK1-ILE368ASN neurons. Our findings suggest the existence of a network onto which pathways associated with PD pathology converge, and offers an inclusive interpretation of the phenotypic heterogeneity of PD. [less ▲]

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See detailGeneration of two human induced pluripotent stem cell lines from fibroblasts of Parkinson’s disease patients carrying the ILE368ASN mutation in PINK1 (LCSBi002) and the R275W mutation in Parkin (LCSBI004)
Novak, Gabriela; Finkbeiner, Steven; Skibinski, Gaia et al

in Stem Cell Research (2022), 61

Mutations in PINK1 and Parkin are two of the main causes of recessive early-onset Parkinson’s disease (PD). We generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of a 64-year-old ... [more ▼]

Mutations in PINK1 and Parkin are two of the main causes of recessive early-onset Parkinson’s disease (PD). We generated human induced pluripotent stem cells (hiPSCs) from fibroblasts of a 64-year-old male patient with a homozygous ILE368ASN mutation in PINK1, who experienced disease onset at 33 years, and from fibroblasts of a 61-year-old female patient heterozygous for the R275W mutation in Parkin, who experienced disease onset at 44 years. Array comparative genomic hybridization (aCGH) determined genotypic variation in each line. The cell lines were successfully used to generate midbrain dopaminergic neurons, the neuron type primarily affected in PD. [less ▲]

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