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See detailInduced pluripotent stem cell line (LCSBi001-A) derived from a patient with Parkinson's disease carrying the p.D620N mutation in VPS35
Larsen, Simone UL; Hanss, Zoé UL; Cruciani, Gérald UL et al

in Stem Cell Research (2020)

Fibroblasts were obtained from a 76 year-old man diagnosed with Parkinson's disease (PD). The disease is caused by a heterozygous p.D620N mutation in VPS35. Induced pluripotent stem cells (iPSCs) were ... [more ▼]

Fibroblasts were obtained from a 76 year-old man diagnosed with Parkinson's disease (PD). The disease is caused by a heterozygous p.D620N mutation in VPS35. Induced pluripotent stem cells (iPSCs) were generated using the CytoTune™-iPS 2.0 Sendai Reprogramming Kit (Thermo Fisher Scientific). The presence of the c.1858G > A base exchange in exon 15 of VPS35 was confirmed by Sanger sequencing. The iPSCs are free of genomically integrated reprogramming genes, express pluripotency markers, display in vitro differentiation potential to the three germ layers and have karyotypic integrity. Our iPSC line will be useful for studying the impact of the p.D620N mutation in VPS35 in vitro. [less ▲]

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See detailDISSECTING GENETIC EPISTASIS IN FAMILIAL PARKINSON’S DISEASE USING A DIGENIC PATIENT-DERIVED STEM CELL MODEL
Hanss, Zoé UL

Doctoral thesis (2019)

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. 10% of PD patients present a familial form of the disease implicating genetic mutations. A variability in terms of ... [more ▼]

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. 10% of PD patients present a familial form of the disease implicating genetic mutations. A variability in terms of disease expressivity, severity and penetrance can be observed among familial cases. The idea that the classical one-gene one-trait model may not catch the full picture of genetic contribution to PD pathophysiology is increasingly recognized. Therefore, a polygenic model where multiple genes would influence the disease risk and the phenotypic traits in PD should be investigated. Mutations in PRKN, encoding the E3 ubiquitin-protein ligase Parkin, cause young onset autosomal recessive forms of PD. A variability in terms of clinical presentation and neuropathology have been observed in PD patients carrying mutations in Parkin. On the other hand, mutations in GBA were recently recognized as the most common genetic risk factor for developing PD. The incomplete penetrance of the disease in patients with GBA mutations may implicate other genetic factors. Therefore, it can be hypothesized that the interactions between common PD genes like PRKN and GBA can contribute to the phenotypic heterogeneity observed in PD cases. To explore this hypothesis, we generated patient-derived cellular models from several PD patients carrying pathogenic mutations in either both PRKN and GBA (triallelic models) or in only one of them (bi- or monoallelic models). We developed a novel strategy to gene edit the N370S mutation in GBA via CRISPR-Cas9, without interference with its respective pseudogene, which allows for the dissection of the role of GBA in the context of a PRKN mutation on an isogenic background. We identified a specific α-synuclein homeostasis in the triallelic model. The genetic and pharmacological rescue of GBA in the triallelic model modified the observed α-synuclein phenotype, proving the contribution of GBA to the observed phenotype. We then investigated whether Parkin was contributing to the phenotype. The modulation of Parkin function in the context of a GBA mutation induced a modification of the α-synuclein homeostasis. We therefore concluded that both PRKN and GBA are influencing α-synuclein homeostasis in the triallelic model. Nevertheless, the phenotypic outcome of the co-occurrence of these mutations was not additive nor synergistic. We therefore suggest the existence of an epistatic interaction between mutant GCase and Parkin that would underlie the clinical heterogeneity observed in PD patients carrying these mutations. [less ▲]

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See detailThe genetic architecture of mitochondrial dysfunction in Parkinson's Disease
Krüger, Rejko UL; Larsen, Simone UL; Hanss, Zoé UL

in Cell and Tissue Research (2018)

Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post mortem ... [more ▼]

Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated to mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, it leads to cell death via apoptosis which defines the cellular level of quality control. Here we review how currently known PD-linked genetic variants interfere with the different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17-23) and some susceptibility variants such as GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants as candidates for PD, such as HSPA9, TRAP1 and RHOT1 complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches. [less ▲]

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