PTPA variants and impaired PP2A activity in early-onset Parkinsonism with intellectual disability

APPENDIX 1 : French and Mediterranean clinicians’ network for Parkinson’s disease genetics (the PDG group) collaborators French PDG collaborators Yves Agid, Mathieu Anheim, Michel Borg, Alexis Brice, Emmanuel Broussolle, Jean-Christophe Corvol, Philippe Damier, Luc Defebvre, Alexandra Dürr, Franck Durif, Jean Luc Houeto, Paul Krack, Stephan Klebe, Suzanne Lesage, Ebba Lohmann, Maria Martinez, Graziella Mangone, Louise-Laure Mariani, Pierre Pollak, Olivier Rascol, François Tison, Christine Tranchant, Marc Vérin, François Viallet, and Marie Vidailhet. Collaborators from Mediterranean countries Ebba Lohmann, Murat Emre, Hasmet Hanagasi, Basar Bilgic, Bedia Marangozoğlu, Mustapha Benmahdjoub, Mohammed Arezki, Sofiane A. Bouchetara, Traki Benhassine, Meriem Tazir, Mouna Ben Djebara, Riadh Gouider, Sawssan Ben Romdhan, Chokri Mhiri, Ahmed Bouhouche.APPENDIX 2 : Collaborators of the International Parkinsonism Genetics Network. Vincenzo Bonifati, Wim Mandemakers, Anneke J. A. Kievit, Agnita J. W. Boon, Joaquim J. Ferreira, Leonor Correia Guedes, Murat Emre, Hasmet A. Hanagasi, Basar Bilgic, Zeynep Tufekcioglu, Bülent Elibol, Okan Doğu, Murat Gultekin, Hsin F. Chien, Egberto Barbosa, Laura Bannach Jardim, Carlos R. M. Rieder, Hsiu-Chen Chang, Chin-Song Lu, Yah-Huei Wu-Chou, Tu-Hsueh Yeh, Leonardo Lopiano, Cristina Tassorelli, Claudio Pacchetti, Cristoforo Comi, Francesco Raudino, Laura Bertolasi, Michele Tinazzi, Alberto Bonizzato, Carlo Ferracci, Roberto Marconi, Marco Guidi, Marco Onofrj, Astrid Thomas, Nicola Vanacore, Giuseppe Meco, Edito Fabrizio, Giovanni Fabbrini, Alfredo Berardelli, Fabrizio Stocchi, Laura Vacca, Paolo Barone, Marina Picillo, Giuseppe De Michele, Chiara Criscuolo, Michele De Mari, Claudia Dell’Aquila, Giovanni Iliceto, Vincenzo Toni, Giorgio Trianni, Valeria Saddi, Gianni Cossu, Maurizio Melis.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 alphasynuclein, 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.The Stichting ParkinsonFonds (The Netherlands); the Fondation pour la Recherche Médicale; PTC Therapeutics, the Fondation de France, France-Parkinson Association, la Fédération pour la Recherche sur le Cerveau (FRC) and the French program ‘Investissements d’avenir’ (ANR-10-IAIHU-06) to AB; and grants from the South African Medical Research Council (Self-Initiated Research Grant) and the National Research Foundation of South Africa.https://academic.oup.com/brainNeurologySDG-03:Good heatlh and well-bein