@article{23f68627df9a4506bcc76b6b53f015af,
title = "Parkinson's Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2-Hydroxypropyl-β-Cyclodextrin Treatment",
abstract = "Background: 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 phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostasis, vesicle trafficking, and autophagy are sufficient to cause PD. Objectives: We sought to evaluate the difference between controls' and PINK1 patients' derived neurons in their transition from neuroepithelial stem cells to neurons, allowing us to identify potential pathways to target with repurposed compounds. Methods: Using two-dimensional and three-dimensional models of patients' derived neurons we recapitulated PD-related phenotypes. We introduced the usage of midbrain organoids for testing compounds. Using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), we corrected the point mutations of three patients' derived cells. We evaluated the effect of the selected compound in a mouse model. Results: PD patient-derived cells presented differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and a reduced differentiation efficiency to tyrosine hydroxylase positive (TH+) neurons compared to controls' cells. Correction of a patient's point mutation ameliorated the metabolic properties and neuronal firing rates as well as reversing the differentiation phenotype, and reducing the increased astrocytic levels. Treatment with 2-hydroxypropyl-β-cyclodextrin increased the autophagy and mitophagy capacity of neurons concomitant with an improved dopaminergic differentiation of patient-specific neurons in midbrain organoids and ameliorated neurotoxicity in a mouse model. Conclusion: We show that treatment with a repurposed compound is sufficient for restoring the impaired dopaminergic differentiation of PD patient-derived cells.",
keywords = "cyclodextrin, isogenics, organoids, Parkinson's disease, PINK1",
author = "Javier Jarazo and Kyriaki Barmpa and Jennifer Modamio and Cl{\'a}udia Saraiva and S{\`o}nia Sabat{\'e}-Soler and Isabel Rosety and Anne Griesbeck and Florian Skwirblies and Gaia Zaffaroni and Smits, {Lisa M.} and Jihui Su and Jonathan Arias-Fuenzalida and Jonas Walter and Gemma Gomez-Giro and Monzel, {Anna S.} and Xiaobing Qing and Armelle Vitali and Gerald Cruciani and Ibrahim Boussaad and Francesco Brunelli and Christian J{\"a}ger and Aleksandar Rakovic and Wen Li and Lin Yuan and Emanuel Berger and Giuseppe Arena and Silvia Bolognin and Ronny Schmidt and Christoph Schr{\"o}der and Antony, {Paul M.A.} and Christine Klein and Rejko Kr{\"u}ger and Philip Seibler and Schwamborn, {Jens C.}",
note = "Funding Information: : This project was funded by the Fonds National de la Recherche (FNR) Luxembourg (CORE, C13/BM/5791363). This is a European Union Joint Program–Neurodegenerative Disease Research (JPND) project (INTER/JPND/14/02; INTER/JPND/15/11092422). This project is also supported by the European Union's Horizon 2020 research and innovation program under grant agreement no. 668738, Systems Medicine of Mitochondrial Parkinson's Disease (SysMedPD). The automated screening platform was supported by a PEARL grant of the FNR to R.K. (FNR/P13/6682797). G.A. is supported by the FNR Mitochondrial Risk factors in Parkinson's Disease (MiRisk‐PD) (C17/BM/11676395). J.J. is supported by a Pelican award from the Fondation du Pelican de Mie et Pierre Hippert‐Faber. J.J., L.M.S., A.S.M., J.W., and X.Q. were supported by FNR Aides {\`a} la Formation‐Recherche. G.G.G. was funded by the Neuronal ceroid lipofuscinosis (NCL)‐Stiftung (Hamburg, Germany). A.R., C.K., and P.S. are supported by the Deutsche Forschungs Gemeinschaft (DFG) (FOR2488). Funding agencies Funding Information: We thank Prof. Dr. Hans R. Sch{\"o}ler of the Max Planck Institute, Dr. Jared Sterneckert of the Center for Regenerative Therapies Dresden, Prof. Dr. Thomas Gasser of the Hertie Institute in T{\"u}bingen, William Skarnes of the Jackson Laboratory, the Coriell Institute for providing cell lines, and Prof. T. Graham and A. Sargsyan from the University of Utah for kindly providing us with the Rosella construct. Gene editing was supported by the flow cytometry core of the Luxembourg Centre for Systems Biomedicine (LCSB) bioimaging platform. Zdenka Hodak of the LCSB Metabolomics Platform for providing technical and analytical support. We thank the Disease Modeling Screening Platform from LCSB and Luxembourg Institute of Health (LIH) for their help with performing automated and high‐throughput procedures. Finally, we also thank the private donors who support our work at the LCSB. Publisher Copyright: {\textcopyright} 2021 International Parkinson and Movement Disorder Society",
year = "2022",
month = jan,
doi = "10.1002/mds.28810",
language = "English",
volume = "37",
pages = "80--94",
journal = "Movement Disorders",
issn = "0885-3185",
publisher = "John Wiley & Sons Inc.",
number = "1",
}