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Development and characterization of disease models of PP2A-related neurodevelopmental disorders, new syndromic variants of severe intellectual disability
Belgium (BeMSA) - KU Leuven, Leuven
Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics
Prof. Veerle Janssens, dr. Saar Reynhout
Prof. Veerle Janssens, dr. Saar Reynhout
Type of Research Project
- Basic science
What is the background of the project?
Neurodevelopmental disorders (NDDs) represent a collection of clinically heterogeneous disorders, including intellectual disability (ID) and epilepsy as well as various behavioral disorders. Recent advances in whole-exome sequencing have highlighted recurrent de novo mutations in genes encoding specific subunits of Type 2A Protein Phosphatase (PP2A) as a new cause of ID (e.g. PPP2R5D, PPP2R1A, PPP2CA). PP2A phosphatases catalyze the dephosphorylation of phospho-Ser and phospho-Thr residues in a large variety of substrates, thereby counterbalancing Ser/Thr-specific protein kinases, and thus playing essential regulatory roles in cellular signaling. Structurally, PP2A phosphatases are holoenzymes, comprising three subunits: a catalytic C-type, a scaffolding A-type and a regulatory B-type, of which the latter is of major importance in determining physiological functions, substrate specificity, and regulation of the complex. Biochemical characterization in our lab revealed that the vast majority of ID-related PPP2R5D variants (encoding the regulatory B56δ subunit) showed decreased binding to the A and C subunits. Given that the regulatory subunit is crucial for interaction with its specific substrates, failure of recruitment of the PP2A holoenzyme could result in the confinement of these substrates, and thus a dominant-negative mode of action.
What is the aim of the project?
In this project, we aim to further unravel the pathological mechanism of ID-related mutations in PPP2R5D, which is a new cause of ID and NDD, discovered by the lab in 2015. To this end, we establish several complementary in vitro and in vivo disease models, of which the phenotype is analyzed.
What techniques and methods are used?
The techniques commonly used in this project are site-directed mutagenesis (‘cloning’ of the mutational variants), transfection (including general cell culture techniques) and lysis of the cells of interest. Followed by immunoprecipitation, western blotting or mass spectrometry, and analysis. Additional techniques could be implemented according to the progress made at the time of the project, including cell signaling studies, phenotypic assays (growth, migration).
What is the role of the student?
- The student will mainly observe
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- If the project includes “lab work”
- the student will take active part in the practical aspect of the project
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student should be able to perform most of the experimental techniques individually by the end of the internship. This includes, but is not limited to: Cell transfection and harvesting, Gel electrophoresis, Western Blotting and developing. They should have a scientific view on the project and be able to draw conclusions based on obtained data. Ideally, they are also able to perform, to some extent, data analysis (with or without active guidance). The student will take active part in the practical part of our research and is encouraged to ask questions.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
The supervisor will provide articles and background information before the start of the project. The student can always ask for additional information if desired.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- No specific outcome is expected
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
The student should be able to work organized, ask (critical) questions and have an enthusiastic attitude.
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system - Students in biomedical fields
- Houge; G.; Haesen; D.; Vissers; L.E.; Mehta; S.; Parker; M.J.; Wright; M.; Vogt; J.; McKee; S.; Tolmie; J.L.; Cordeiro; N.; et al. (2015). B56d-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. J. Clin. Invest. 125; 3051–3062
- Reynhout S; Jansen S; Haesen D; et al. (2019) De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A; PPP2CA; Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders. Am J Hum Genet. 104; 139-156 [published correction appears in Am J Hum Genet. 2019;104:357].
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