Parkinson's Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2-Hydroxypropyl-β-Cyclodextrin Treatment

Javier Jarazo; Kyriaki Barmpa; Jennifer Modamio; Cláudia Saraiva; Sònia Sabaté-Soler; Isabel Rosety; Anne Griesbeck; Florian Skwirblies; Gaia Zaffaroni; Lisa M. Smits; Jihui Su; Jonathan Arias-Fuenzalida; Jonas Walter; Gemma Gomez-Giro; Anna S. Monzel; Xiaobing Qing; Armelle Vitali; Gerald Cruciani; Ibrahim Boussaad; Francesco Brunelli; Christian Jäger; Aleksandar Rakovic; Wen Li; Lin Yuan; Emanuel Berger; Giuseppe Arena; Silvia Bolognin; Ronny Schmidt; Christoph Schröder; Paul M.A. Antony; Christine Klein; Rejko Krüger; Philip Seibler; Jens C. Schwamborn

doi:10.1002/mds.28810

Parkinson's Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2-Hydroxypropyl-β-Cyclodextrin Treatment

Javier Jarazo, Kyriaki Barmpa, Jennifer Modamio, Cláudia Saraiva, Sònia Sabaté-Soler, Isabel Rosety, Anne Griesbeck, Florian Skwirblies, Gaia Zaffaroni, Lisa M. Smits, Jihui Su, Jonathan Arias-Fuenzalida, Jonas Walter, Gemma Gomez-Giro, Anna S. Monzel, Xiaobing Qing, Armelle Vitali, Gerald Cruciani, Ibrahim Boussaad, Francesco BrunelliChristian Jäger, Aleksandar Rakovic, Wen Li, Lin Yuan, Emanuel Berger, Giuseppe Arena, Silvia Bolognin, Ronny Schmidt, Christoph Schröder, Paul M.A. Antony, Christine Klein, Rejko Krüger, Philip Seibler, Jens C. Schwamborn^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Neurogenetik

62 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Movement Disorders
Jahrgang	37
Ausgabenummer	1
Seiten (von - bis)	80-94
Seitenumfang	15
ISSN	0885-3185
DOIs	https://doi.org/10.1002/mds.28810
Publikationsstatus	Veröffentlicht - 01.2022

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: 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 à 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 We thank Prof. Dr. Hans R. Schöler of the Max Planck Institute, Dr. Jared Sterneckert of the Center for Regenerative Therapies Dresden, Prof. Dr. Thomas Gasser of the Hertie Institute in Tübingen, 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.

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SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Querschnittsbereich: Medizinische Genetik

DFG-Fachsystematik

2.23-02 Molekulare Biologie und Physiologie von Nerven und Gliazellen

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10.1002/mds.28810

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Jarazo, J., Barmpa, K., Modamio, J., Saraiva, C., Sabaté-Soler, S., Rosety, I., Griesbeck, A., Skwirblies, F., Zaffaroni, G., Smits, L. M., Su, J., Arias-Fuenzalida, J., Walter, J., Gomez-Giro, G., Monzel, A. S., Qing, X., Vitali, A., Cruciani, G., Boussaad, I., ... Schwamborn, J. C. (2022). Parkinson's Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2-Hydroxypropyl-β-Cyclodextrin Treatment. Movement Disorders, 37(1), 80-94. https://doi.org/10.1002/mds.28810

@article{314f9121bb614bfd82a2a51a9ea18854,

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.",

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 = "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",

}

Jarazo, J, Barmpa, K, Modamio, J, Saraiva, C, Sabaté-Soler, S, Rosety, I, Griesbeck, A, Skwirblies, F, Zaffaroni, G, Smits, LM, Su, J, Arias-Fuenzalida, J, Walter, J, Gomez-Giro, G, Monzel, AS, Qing, X, Vitali, A, Cruciani, G, Boussaad, I, Brunelli, F, Jäger, C, Rakovic, A, Li, W, Yuan, L, Berger, E, Arena, G, Bolognin, S, Schmidt, R, Schröder, C, Antony, PMA, Klein, C, Krüger, R, Seibler, P & Schwamborn, JC 2022, 'Parkinson's Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2-Hydroxypropyl-β-Cyclodextrin Treatment', Movement Disorders, Jg. 37, Nr. 1, S. 80-94. https://doi.org/10.1002/mds.28810

TY - JOUR

T1 - Parkinson's Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2-Hydroxypropyl-β-Cyclodextrin Treatment

AU - Jarazo, Javier

AU - Barmpa, Kyriaki

AU - Modamio, Jennifer

AU - Saraiva, Cláudia

AU - Sabaté-Soler, Sònia

AU - Rosety, Isabel

AU - Griesbeck, Anne

AU - Skwirblies, Florian

AU - Zaffaroni, Gaia

AU - Smits, Lisa M.

AU - Su, Jihui

AU - Arias-Fuenzalida, Jonathan

AU - Walter, Jonas

AU - Gomez-Giro, Gemma

AU - Monzel, Anna S.

AU - Qing, Xiaobing

AU - Vitali, Armelle

AU - Cruciani, Gerald

AU - Boussaad, Ibrahim

AU - Brunelli, Francesco

AU - Jäger, Christian

AU - Rakovic, Aleksandar

AU - Li, Wen

AU - Yuan, Lin

AU - Berger, Emanuel

AU - Arena, Giuseppe

AU - Bolognin, Silvia

AU - Schmidt, Ronny

AU - Schröder, Christoph

AU - Antony, Paul M.A.

AU - Klein, Christine

AU - Krüger, Rejko

AU - Seibler, Philip

AU - Schwamborn, Jens C.

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85116901538

UR - https://www.mendeley.com/catalogue/41821d3b-f99f-3b7f-ba4a-53b4b365254f/

U2 - 10.1002/mds.28810

DO - 10.1002/mds.28810

M3 - Journal articles

C2 - 34637165

AN - SCOPUS:85116901538

SN - 0885-3185

VL - 37

SP - 80

EP - 94

JO - Movement Disorders

JF - Movement Disorders

IS - 1

ER -

Parkinson's Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2-Hydroxypropyl-β-Cyclodextrin Treatment

Abstract

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