PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability
Authors: Fevga Christina , Tesson Christelle , Carreras Mascaro Ana , Courtin Thomas , van Coller Riaan , Sakka Salma , Ferraro Federico , Farhat Nouha , Bardien Soraya , Damak Mariem , Carr Jonathan , Ferrien Mélanie , Boumeester Valerie , Hundscheid Jasmijn , Grillenzoni Nicola , Kessissoglou Irini A , Kuipers Demy J S , Quadri Marialuisa ,   French and Mediterranean Parkinson disease Genetics Study Group, 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 ,   International Parkinsonism Genetics Network, 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-Christophe , Mhiri Chokri , Hassan Bassem A , Breedveld Guido J , Lesage Suzanne , Mandemakers Wim , Brice Alexis , Bonifati Vincenzo 
Published: September 2022

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&gt;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&gt;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.