Mechanism-Guided Therapeutic Targeting in Knock-in Mouse Models of PPP2R5D-Associated Neurodevelopmental Disorder (Abstract ID: 272615)

Tehreem Haider; Chian Ju Jong; Chunling Chen; Stefan Strack

doi:10.1016/j.jpet.2026.104829

Houge-Janssens-Syndrome 1 (aka Jordan’s Syndrome, JS) is a rare neurodevelopmental disorder caused by de novo missense mutation in the PPP2R5D gene, which encodes the B56δ regulatory subunit of the PP2A complex. This disorder is marked by developmental delay, cognitive impairment, and autism. PP2A regulatory subunits are responsible for determining enzyme localization and substrate specificity. Currently, there are no approved disease-modifying therapies for JS. Therefore, to enable a mechanism-guided therapeutic evaluation, we generated a knock-in mouse models with JS mutations (E198K, E420K). In this study, we employed a mechanism-guided approach to screen two pharmacologically distinct therapeutic candidates targeting complementary neural pathways. Zatolmilast, a selective PDE4D inhibitor, was chosen to enhance cAMP signalling, which is involved in synaptic plasticity and gene regulation. R-baclofen, a GABA-B receptor agonist, was selected to modulate inhibitory neurotransmission and network excitability. The behavioural assessment of E198K and E420K mice was conducted using a battery of behavioural assays, including the Open field test to evaluate locomotor activity and sedation, the 2-Trial Y-maze to assess short term memory, the Nestlet shredding/nest building assay, and the Phenotyper home cage system to quantify innate home cage behaviour, locomotor activity, and circadian activity patterns. The JS mouse models demonstrated robust deficits in cognition, home cage behaviours, and activity patterns, consistent with clinical manifestations observed in patients. Zatolmilast treatment improved cognitive deficits and reduced hyperactivity, reflecting that cAMP pathway modulation can be a viable therapeutic strategy for Jordan Syndrome. In contrast, R-baclofen failed to rescue the cognitive impairment and hyperactivity in E198K mice. Acute R-baclofen produced a dose-dependent sedation, which could be overcome with repeated dose administration. However, R-baclofen did not result in sustained improvements in cognitive and hyperactivity behaviours. Together, these findings demonstrate that PPP2R5D mutations contribute to neurodevelopmental disorders by disruption of the PP2A-regulated signalling pathways. The E198K and E420K knock-in models recapitulate the significant clinical representation of this disorder and serves as a valuable model for therapeutic evaluation. Importantly, pharmacological modulation of pathways can differentially influence disease-relevant phenotypes. These results highlight the importance of pathway-specific and mechanism-guided drug selection and support continued exploration of cAMP-targeted therapies for Jordan Syndrome.

Mechanism-Guided Therapeutic Targeting in Knock-in Mouse Models of PPP2R5D-Associated Neurodevelopmental Disorder (Abstract ID: 272615)

View Online

Abstract

Details

Metrics