[en] The complex and heterogeneous nature of Parkinson's disease (PD) is still not fully understood. However, increasing evidence supports mitochondrial impairment as a major driver of neurodegeneration. Miro1, a mitochondrial GTPase encoded by the RHOT1 gene, is involved in mitochondrial transport, mitophagy and mitochondrial calcium buffering, and is therefore essential for maintaining mitochondrial homeostasis. Recently, Miro1 has been linked genetically and pathophysiologically to PD, further supported by the identification of heterozygous variants of Miro1 in patients. Herein, we used patient-derived cellular models alongside knock-in mice to investigate Miro1-dependent pathophysiological processes and molecular mechanisms underlying neurodegeneration in PD. Experimental work performed in induced pluripotent stem cell (iPSC)-derived models, including midbrain organoids and dopaminergic neuronal cell cultures from a PD patient carrying the p.R272Q Miro1 mutation as well as healthy and isogenic controls, indicated that the p.R272Q Miro1 mutation leads to increased oxidative stress, disrupted mitochondrial bioenergetics and altered cellular metabolism. These changes were accompanied by increased α-synuclein levels and a significant reduction of dopaminergic neurons. Moreover, the p.R272Q Miro1 mutation-located in the calcium-binding domain of the GTPase-disrupted calcium homeostasis, resulting in calcium-dependent activation of calpain proteases and the subsequent cleavage of α-synuclein. Knock-in mice expressing p.R285Q Miro1 (the murine orthologue of the human p.R272Q mutation) displayed accumulation of phosphorylated α-synuclein in the striatum and a significant loss of dopaminergic neurons in the substantia nigra pars compacta, accompanied by behavioural alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypes in vitro and in vivo, reinforcing its pivotal role in PD pathogenesis.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
CHEMLA, Axel ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER
SACRIPANTI, Ginevra ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
BARMPA, Kyriaki ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
ZAGARE, Alise ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
GARCIA, Pierre ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Neuroinflammation Group > Team Manuel BUTTINI ; Luxembourg Center of Neuropathology (LCNP), Laboratoire National de Santé, L-3555, Dudelange, Luxembourg
GORGOGIETAS, Vyron ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
ANTONY, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Imaging Platform
OHNMACHT, Jochen ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), L-1445 Strassen, Luxembourg
BARON, Alexandre ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER
Jung, Jaqueline; Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany
Lind-Holm Mogensen, Frida; Faculty of Science, Technology and Medicine, University of Luxembourg, L-4365 Esch-sur-Alzette, Luxembourg ; Department of Cancer Research, Luxembourg Institute of Health (LIH), L-1210 Luxembourg, Luxembourg
MICHELUCCI, Alessandro ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Scientific Central Services > Disease Modelling and Screening Platform ; Department of Cancer Research, Luxembourg Institute of Health (LIH), L-1210 Luxembourg, Luxembourg
MARZESCO, Anne-Marie ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Scientific Central Services
BUTTINI, Manuel ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Neuroinflammation Group ; Luxembourg Center of Neuropathology (LCNP), Laboratoire National de Santé, L-3555, Dudelange, Luxembourg
Schmidt, Thorsten ; Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany
GRÜNEWALD, Anne ; University of Luxembourg ; Institute of Neurogenetics, University of Lübeck, 160 Lübeck, Germany
SCHWAMBORN, Jens Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), L-1445 Strassen, Luxembourg ; Parkinson Research Clinic, Centre Hospitalier de Luxembourg, L-1210, Luxembourg, Luxembourg
SARAIVA, Claudia ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
C19/BM/13535609, C.S. C17/BM/11676395, R.K., A.G. and G.A FNR/P13/6682797 PRIDE17/12244779/PARK-QC C21/BM/15850547 FNR9631103 - Model IPD - Modelling Idiopathic Parkinson’S Disease-associated Somatic Variation In Dopaminergic Neurons, 2015 (01/01/2016-31/12/2022) - Anne Grünewald PRIDE/14254520/I2TRON P16/BM/11192868
Funders :
Fonds National de la Recherche Luxembourg Michael J. Fox Foundation Horizon 2020
Funding text :
This work was primarily supported by Fonds National de la Recherche Luxembourg (FNR) under the CORE Programmes (C19/BM/13535609, C.S. and J.C.S.; C17/BM/11676395, R.K., A.G. and G.A). R.K. also obtained funding from the FNR PEARL Excellence Programme (FNR/P13/6682797), the Michael J. Fox Foundation and the European Union Horizon 2020 programme (WIDESPREAD; CENTRE-PD; grant 692320). A.C., G.A., A.G., and F.L-H.M. were supported by the FNR PARK-QC Doctoral Training Unit (PRIDE17/12244779/PARK-QC), FNR CORE grant C21/BM/15850547, FNR ATTRACT programme FNR9631103 and FNR-PRIDE programme i2TRON (PRIDE/14254520/I2TRON), respectively. Authors acknowledge Prof. Michel Mittelbronn funded by FNR PEARL programme (P16/BM/11192868).
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