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See detailMitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons
Hanss, Zoé UL; Larsen, Simone UL; Antony, Paul UL et al

in Movement Disorders (2020)

Background: VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation ... [more ▼]

Background: VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation of mitochondrial proteins via mitochondria-derived vesicles. The p.D620N mutation of VPS35 causes an autosomal-dominant form of Parkinson’s disease (PD), clinically representing typical PD. Objective: Most of the studies on p.D620N VPS35 were performed on human tumor cell lines, rodent models overexpressing mutant VPS35, or in patient-derived fibroblasts. Here, based on identified target proteins, we investigated the implication of mutant VPS35 in autophagy, lysosomal degradation, and mitochondrial function in induced pluripotent stem cell-derived neurons from a patient harboring the p.D620N mutation. Methods: We reprogrammed fibroblasts from a PD patient carrying the p.D620N mutation in the VPS35 gene and from two healthy donors in induced pluripotent stem cells. These were subsequently differentiated into neuronal precursor cells to finally generate midbrain dopaminergic neurons. Results: We observed a decreased autophagic flux and lysosomal mass associated with an accumulation of α-synuclein in patient-derived neurons compared to controls. Moreover, patient-derived neurons presented a mitochondrial dysfunction with decreased membrane potential, impaired mitochondrial respiration, and increased production of reactive oxygen species associated with a defect in mitochondrial quality control via mitophagy. Conclusion: We describe for the first time the impact of the p.D620N VPS35 mutation on autophago-lysosome pathway and mitochondrial function in stem cell-derived neurons from an affected p.D620N carrier and define neuronal phenotypes for future pharmacological interventions [less ▲]

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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 detailPHENOTYPIC CHARACTERIZATION OF CELLULAR MODELS OF VPS35-ASSOCIATED MUTATION IN PARKINSON’S DISEASE
Larsen, Simone UL

Doctoral thesis (2019)

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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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