Stem Cell Reports (Nov 2018)
Mitochondrial Dysregulation and Impaired Autophagy in iPSC-Derived Dopaminergic Neurons of Multiple System Atrophy
- Giacomo Monzio Compagnoni,
- Giulio Kleiner,
- Maura Samarani,
- Massimo Aureli,
- Gaia Faustini,
- Arianna Bellucci,
- Dario Ronchi,
- Andreina Bordoni,
- Manuela Garbellini,
- Sabrina Salani,
- Francesco Fortunato,
- Emanuele Frattini,
- Elena Abati,
- Christian Bergamini,
- Romana Fato,
- Silvia Tabano,
- Monica Miozzo,
- Giulia Serratto,
- Maria Passafaro,
- Michela Deleidi,
- Rosamaria Silipigni,
- Monica Nizzardo,
- Nereo Bresolin,
- Giacomo P. Comi,
- Stefania Corti,
- Catarina M. Quinzii,
- Alessio Di Fonzo
Affiliations
- Giacomo Monzio Compagnoni
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Giulio Kleiner
- Department of Neurology, Columbia University, New York, NY 10032, USA
- Maura Samarani
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan 20090, Italy
- Massimo Aureli
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan 20090, Italy
- Gaia Faustini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy
- Arianna Bellucci
- Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy
- Dario Ronchi
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Andreina Bordoni
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Manuela Garbellini
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Sabrina Salani
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Francesco Fortunato
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Emanuele Frattini
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Elena Abati
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Christian Bergamini
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna 40126, Italy
- Romana Fato
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna 40126, Italy
- Silvia Tabano
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy; Division of Pathology, IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan 20122, Italy
- Monica Miozzo
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy; Division of Pathology, IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan 20122, Italy
- Giulia Serratto
- CNR Institute of Neuroscience, Department BIOMETRA, Università degli Studi di Milano, Milan 20129, Italy
- Maria Passafaro
- CNR Institute of Neuroscience, Department BIOMETRA, Università degli Studi di Milano, Milan 20129, Italy
- Michela Deleidi
- German Center for Neurodegenerative Diseases (DZNE), Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller Straße 23, Tübingen 72076, Germany
- Rosamaria Silipigni
- Laboratory of Medical Genetics, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
- Monica Nizzardo
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Nereo Bresolin
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Giacomo P. Comi
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Stefania Corti
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
- Catarina M. Quinzii
- Department of Neurology, Columbia University, New York, NY 10032, USA
- Alessio Di Fonzo
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy; Corresponding author
- Journal volume & issue
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Vol. 11,
no. 5
pp. 1185 – 1198
Abstract
Summary: Multiple system atrophy (MSA) is a progressive neurodegenerative disease that affects several areas of the CNS, whose pathogenesis is still widely unclear and for which an effective treatment is lacking. We have generated induced pluripotent stem cell-derived dopaminergic neurons from four MSA patients and four healthy controls and from two monozygotic twins discordant for the disease. In this model, we have demonstrated an aberrant autophagic flow and a mitochondrial dysregulation involving respiratory chain activity, mitochondrial content, and CoQ10 biosynthesis. These defective mechanisms may contribute to the onset of the disease, representing potential therapeutic targets. : Monzio Compagnoni et al. present an iPSC-based neuronal in vitro model of multiple system atrophy. Patients' dopaminergic neurons display a dysregulation of mitochondrial functioning and autophagy, suggesting new hints for the comprehension of the pathogenesis of the disease. Keywords: multiple system atrophy, induced pluripotent stem cells, dopaminergic neurons, mitochondria, autophagy, MSA, neurodegeneration
