Parkinson's disease phenotypes in patient specific brain organoids are improved by HP-β-CD treatment

The etiology of Parkinson's disease (PD) is only partially understood despite the fact that environmental causes, risk factors, and specific gene mutations are contributors to the disease. Biallelic mutations in the PTEN-induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostas...

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Published inbioRxiv
Main Authors Barmpa, Kyriaki, Rosety, Isabel, Smits, Lisa M, Arias-Fuenzalida, Jonathan, Jonas, Walter, Gomez-Giro, Gemma, Monzel, Anna S, Qing, Xiaobing, Cruciani, Gerald, Ibrahim Boussaad, Jaeger, Christian, Rakovic, Aleksandar, Berger, Emanuel, Antony, Paul, Klein, Christine, Krüger, Rejko, Seibler, Philip, Jarazo, Javier, Schwamborn, Jens C, Bolognin, Silvia
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 22.10.2019
Subjects
Apoptosis
Autophagy
Cell differentiation
Cell proliferation
CRISPR
Dopamine receptors
Etiology
Homeostasis
Mesencephalon
Mitochondria
Movement disorders
Mutation
Neurodegenerative diseases
Neurons
Organoids
Parkinson's disease
Parkinsons disease
Phagocytosis
Phenotypes
Point mutation
PTEN protein
PTEN-induced putative kinase
Risk factors
β-Cyclodextrin
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Summary:The etiology of Parkinson's disease (PD) is only partially understood despite the fact that environmental causes, risk factors, and specific gene mutations are contributors to the disease. Biallelic mutations in the PTEN-induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostasis, vesicle trafficking, and autophagy, are sufficient to cause PD. By comparing PD patient-derived cells, we show differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and a reduced differentiation efficiency to dopaminergic neurons compared to control cells. Using CRISPR/Cas9 gene editing, correction of a patient's point mutation ameliorated the metabolic properties and neuronal firing rates but without reversing the differentiation phenotype. However, treatment with 2-Hydroxypropyl-β-Cyclodextrin (HP-β-CD) increased the mitophagy capacity of neurons leading to an improved dopaminergic differentiation of patient specific neurons in midbrain organoids. In conclusion, we show that treatment with a repurposed compound is sufficient for restoring dopaminergic differentiation of PD patient-derived cells.
DOI:10.1101/813089