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PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability
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 varia...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10115167/ https://www.ncbi.nlm.nih.gov/pubmed/36073231 http://dx.doi.org/10.1093/brain/awac326 |
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author | 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 Corvol, Jean-Christophe Mhiri, Chokri Hassan, Bassem A Breedveld, Guido J Lesage, Suzanne Mandemakers, Wim Brice, Alexis Bonifati, Vincenzo |
author_facet | 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 Corvol, Jean-Christophe Mhiri, Chokri Hassan, Bassem A Breedveld, Guido J Lesage, Suzanne Mandemakers, Wim Brice, Alexis Bonifati, Vincenzo |
author_sort | Fevga, Christina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10115167 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-101151672023-04-20 PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability 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 Corvol, Jean-Christophe Mhiri, Chokri Hassan, Bassem A Breedveld, Guido J Lesage, Suzanne Mandemakers, Wim Brice, Alexis Bonifati, Vincenzo Brain Original Article 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. Oxford University Press 2022-09-08 /pmc/articles/PMC10115167/ /pubmed/36073231 http://dx.doi.org/10.1093/brain/awac326 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Article 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 Corvol, Jean-Christophe Mhiri, Chokri Hassan, Bassem A Breedveld, Guido J Lesage, Suzanne Mandemakers, Wim Brice, Alexis Bonifati, Vincenzo PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability |
title |
PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability |
title_full |
PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability |
title_fullStr |
PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability |
title_full_unstemmed |
PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability |
title_short |
PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability |
title_sort | ptpa variants and impaired pp2a activity in early-onset parkinsonism with intellectual disability |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10115167/ https://www.ncbi.nlm.nih.gov/pubmed/36073231 http://dx.doi.org/10.1093/brain/awac326 |
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