PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability
Author:
Fevga Christina1ORCID, Tesson Christelle2, Carreras Mascaro Ana1ORCID, Courtin Thomas23ORCID, van Coller Riaan4ORCID, Sakka Salma5, Ferraro Federico1ORCID, Farhat Nouha5, Bardien Soraya67ORCID, Damak Mariem5ORCID, Carr Jonathan8ORCID, Ferrien Mélanie2, Boumeester Valerie1, Hundscheid Jasmijn1, Grillenzoni Nicola2, Kessissoglou Irini A2ORCID, Kuipers Demy J S1ORCID, Quadri Marialuisa1, Agid Yves, Anheim Mathieu, Borg Michel, Brice Alexis, Broussolle Emmanuel, Corvol Jean-Christophe, Damier Philippe, Defebvre Luc, Dürr Alexandra, Durif Franck, Houeto Jean Luc, Krack Paul, Klebe Stephan, Lesage Suzanne, Lohmann Ebba, Martinez Maria, Mangone Graziella, Mariani Louise-Laure, Pollak Pierre, Rascol Olivier, Tison François, Tranchant Christine, Vérin Marc, Viallet François, Vidailhet Marie, Lohmann Ebba, Emre Murat, Hanagasi Hasmet, Bilgic Basar, lu Bedia Marangozog, Benmahdjoub Mustapha, Arezki Mohammed, Bouchetara Sofiane A, Benhassine Traki, Tazir Meriem, Djebara Mouna Ben, Gouider Riadh, Romdhan Sawssan Ben, Mhiri Chokri, Bouhouche Ahmed, Bonifati Vincenzo, Mandemakers Wim, Kievit Anneke J A, Boon Agnita J W, Ferreira Joaquim J, Guedes Leonor Correia, Emre Murat, Hanagasi Hasmet A, Bilgic Basar, Tufekcioglu Zeynep, Elibol Bulent, Dog.u Okan, Gultekin Murat, Chien Hsin F, Barbosa Egberto, Jardim Laura Bannach, Rieder Carlos R M, Chang Hsiu-Chen, Lu Chin-Song, Wu-Chou Yah-Huei, Yeh Tu-Hsueh, Lopiano Leonardo, Tassorelli Cristina, Pacchetti Claudio, Comi Cristoforo, Raudino Francesco, Bertolasi Laura, Tinazzi Michele, Bonizzato Alberto, Ferracci Carlo, Marconi Roberto, Guidi Marco, Onofrj Marco, Thomas Astrid, Vanacore Nicola, Meco Giuseppe, Fabrizio Edito, Fabbrini Giovanni, Berardelli Alfredo, Stocchi Fabrizio, Vacca Laura, Barone Paolo, Picillo Marina, De Michele Giuseppe, Criscuolo Chiara, De Mari Michele, Dell’Aquila Claudia, Iliceto Giovanni, Toni Vincenzo, Trianni Giorgio, Saddi Valeria, Cossu Gianni, Melis Maurizio, Corvol Jean-Christophe29ORCID, Mhiri Chokri5ORCID, Hassan Bassem A2ORCID, Breedveld Guido J1ORCID, Lesage Suzanne2, Mandemakers Wim1ORCID, Brice Alexis23ORCID, Bonifati Vincenzo1ORCID, ,
Affiliation:
1. Department of Clinical Genetics, Erasmus University Medical Center Rotterdam, Erasmus MC , 3015 GD Rotterdam , The Netherlands 2. Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Sorbonne Université , Paris , France 3. Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Génétique, DMU BioGeM , Paris , France 4. Department of Neurology, Faculty of Health Sciences, University of Pretoria , Pretoria , South Africa 5. Research Unit in Neurogenetics, Clinical Investigation Center (CIC) at the CHU Habib Bourguiba , Sfax , Tunisia 6. Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town , South Africa 7. South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Stellenbosch University , Cape Town , South Africa 8. Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town , South Africa 9. Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre d'Investigation Clinique Neurosciences, DMU Neuroscience , Paris , France
Abstract
Abstract
The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability.
We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster.
We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C>A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus.
In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment.
We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.
Funder
Stichting ParkinsonFonds Fondation pour la Recherche Médicale Fondation de France France-Parkinson Association Fédération pour la Recherche sur le Cerveau South African Medical Research Council National Research Foundation of South Africa
Publisher
Oxford University Press (OUP)
Subject
Neurology (clinical)
Cited by
6 articles.
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