Etiology and Molecular Mechanisms of PPP2R5D-Related Developmental Disorders

Author

Chenchen LiFollow

Date of Award

12-2024

Document Type

Dissertation

Degree Name

Ph.D.

Department

Basic Medical Sciences

Committee Chair

Richard E. Honkanen

Advisor(s)

Mark Gillespie, Mark Swingle, Robert Barrington, Wito Richter

Abstract

This dissertation is focused on unraveling the molecular mechanisms underlying PPP2R5D-related intellectual disability, known as Jordan's Syndrome, using comprehensive proteomic and phosphoproteomic analysis. PPP2R5D encodes one of the 16 regulatory subunits of the protein phosphatase 2A (PP2A) holoenzyme, a key regulator involved in critical cellular processes such as cell growth, differentiation, and apoptosis. De novo single nucleotide mutations in PPP2R5D, including E198K and E420K, are believed to potentially disrupt PP2A function and lead to aberrant signaling. These mutations are definitively contributing to the pathogenesis of neurodevelopmental disorders such as Jordan's Syndrome, which characterized by intellectual disability, seizures, hypotonia, autism spectrum disorders, global developmental delays, macrocephaly, and dysmorphic facial features. In this study, we utilized TMT-LC-MS³ technology and bioinformatic approaches to analyzed HEK293 and neural stem cell (NSC) models carrying specific mutations associated with Jordan’s Syndrome (PPP2R5D E198K and E420K), alongside PIK3CA-Related Overgrowth Spectrum (PROS)-related variants (PIK3CA H1047R and MTOR T1977I). The analysis revealed significant alterations in key signaling pathways, highlighting differential phosphorylation patterns in the PI3K-AKT and MEK-ERK-RSK axis, with downstream effectors such as RPS6 and eIF4B exhibiting variant-specific changes. Additionally, we identified a significant impact on spliceosome-associated proteins, linking aberrant splicing with the pathogenesis of neurodevelopmental disorders. Dysregulation of hnRNP A1 phosphorylation, which plays a role in Tau splicing, was particularly evident, suggesting a mechanistic connection between PPP2R5D dysfunction and neuronal impairments. This work provides insights into the molecular etiology of PPP2R5D-related neurodevelopmental disorders. Future directions include increasing phosphopeptide coverage, validating key proteins and pathways through biochemical assays, and exploring potential therapeutic targets to mitigate the effects of PPP2R5D mutations.

Recommended Citation

Li, Chenchen, "Etiology and Molecular Mechanisms of PPP2R5D-Related Developmental Disorders" (2024). Theses and Dissertations. 206.
https://jagworks.southalabama.edu/theses_diss/206