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

Christina Fevga, Christelle Tesson, International Parkinsonism Genetics Network,, Mediterranean Parkinson disease Genetics Study Group, Ana Carreras Mascaro, Thomas Courtin, Riaan Van Coller, Salma Sakka, Federico Ferraro, Nouha Farhat, Soraya Bardien, Mariem Damak, Jonathan Carr, Valerie Boumeester, Jasmijn Hundscheid, Nicola Grillenzoni, Demy J.S. Kuipers, Marialuisa Quadri, Vincenzo Bonifati*, Wim MandemakersWim Mandemakers, Vincenzo Bonifati*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)1496-1510
Number of pages15
Issue number4
Publication statusPublished - Apr 2023

Bibliographical note

This work was supported by a grant (SPF-1870) from the Stichting
ParkinsonFonds (The Netherlands) to VB; the Fondation pour la
Recherche Médicale (FRM, MND202004011718), 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 (Grant Number 129249) to SB.

Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.


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