Abstract
PPP2R5D E420K Mutation in GABAergic Neurons Drives Behaviral but not Developmental Abnormalities in a Mouse Model of Houge-Jassens-Syndrome-1 (Abstract ID: 273358)
The Journal of pharmacology and experimental therapeutics, Vol.393(5), 104833
05/2026
DOI: 10.1016/j.jpet.2026.104833
Abstract
Houge-Janssens-Syndrome 1 (aka Jordan’s Syndrome, JS) is caused by de novo mutations in protein phosphatase 2A (PP2A) regulatory subunit PPP2R5D, leading to intellectual disability with developmental delay. Most pathogenic PPP2R5D variants are charge-reversal missense mutations, e.g. E198K, E420K. However, cell-specific mechanisms underlying disease phenotypes remain poorly understood.
Our previous evidence suggests a PP2A gain-of-function mechanism in JS, leading to dephosphorylation of protein kinase A (PKA) substrates in the brain. We therefore evaluated the therapeutic potential of phosphodiesterase 4 (PDE4) inhibition. Indeed, pharmacological elevation of cAMP ameliorated cognitive and hyperactivity deficits in global E198K and E420K disease models. To determine contributions of inhibitory neurons to disease pathogenesis, we generated conditional E420K knock-in mice and crossed them to Gad2-Cre mice to induce the mutation only in GABAergic neurons (Gad2-E420K).
While newborn developmental milestones were normal for Gad2-E420K mice, adult mice exhibited robust cognitive deficits and hyperactivity, suggesting intact neurodevelopment but interneuron dysfunction that emerges later in life.
We are currently generating Gad2-E420K mice that allow us to interrogate the translatome and (phospho)proteome in wild-type vs JS mutant interneurons.
Our findings suggest that selective disruption of PP2A signaling in GABAergic neurons is sufficient to drive behavioral abnormalities and establish a framework for cell-specific analysis and therapeutic targeting.
Details
- Title: Subtitle
- PPP2R5D E420K Mutation in GABAergic Neurons Drives Behaviral but not Developmental Abnormalities in a Mouse Model of Houge-Jassens-Syndrome-1 (Abstract ID: 273358)
- Creators
- Ruiqi Lyu - Univ of IowaChian Ju Jong - University of IowaChunling Chen - University of South FloridaStefan Strack - University of Iowa
- Resource Type
- Abstract
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.393(5), 104833
- DOI
- 10.1016/j.jpet.2026.104833
- ISSN
- 0022-3565
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 05/2026
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
- Record Identifier
- 9985163461702771
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