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

  • Brain. 2023 Apr 19;146(4):1496-1510. doi: 10.1093/brain/awac326.
Christina Fevga  1 ,  Christelle Tesson  2 ,  Ana Carreras Mascaro  1 ,  Thomas Courtin  2  3 ,  Riaan van Coller  4 ,  Salma Sakka  5 ,  Federico Ferraro  1 ,  Nouha Farhat  5 ,  Soraya Bardien  6  7 ,  Mariem Damak  5 ,  Jonathan Carr  8 ,  Mélanie Ferrien  2 ,  Valerie Boumeester  1 ,  Jasmijn Hundscheid  1 ,  Nicola Grillenzoni  2 ,  Irini A Kessissoglou  2 ,  Demy J S Kuipers  1 ,  Marialuisa Quadri  1 ,  French and Mediterranean Parkinson disease Genetics Study Group ,  International Parkinsonism Genetics Network ,  Jean-Christophe Corvol  2  9 ,  Chokri Mhiri  5 ,  Bassem A Hassan  2 ,  Guido J Breedveld  1 ,  Suzanne Lesage  2 ,  Wim Mandemakers  1 ,  Alexis Brice  2  3 ,  Vincenzo Bonifati  1
Affiliations
  • 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.
PMID: 36073231 DOI: 10.1093/brain/awac326
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.

Keywords
PP2A; PPP2R4; PTPA; intellectual disability; parkinsonism.