Abstract
Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of ubiquitin-protein ligase E3A (UBE3A), resulting in marked changes in synaptic plasticity. In AS mice, a dysregulation of Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) was previously described. This has been convincingly validated through genetic rescue of prominent phenotypes in mouse cross-breeding experiments. Selective ligands that specifically stabilize the CaMKIIα central association (hub) domain and affect different conformational states in vitro are now available. Two of these ligands, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and (E)-2-(5-hydroxy-2-phenyl-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (Ph-HTBA), confer neuroprotection after ischemic stroke in mice where CaMKIIα is known to be dysregulated. Here, we sought to investigate whether pharmacological modulation with these prototypical CaMKIIα hub ligands presents a viable approach to alleviate AS symptoms. We performed an in vivo functional evaluation of AS mice treated for a total of 14 days with either HOCPCA or Ph-HTBA (7 days pre-treatment and 7 days of behavioural assessment). Both compounds were well-tolerated but unable to revert robust phenotypes of motor performance, anxiety, repetitive behaviour or seizures in AS mice. Biochemical experiments subsequently assessed CaMKIIα autophosphorylation in AS mouse brain tissue. Taken together our results indicate that pharmacological modulation of CaMKIIα via the selective hub ligands used here is not a viable treatment strategy in AS.
Original language | English |
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Article number | e14112 |
Journal | Basic and Clinical Pharmacology and Toxicology |
Volume | 136 |
Issue number | 1 |
ISSN | 1742-7835 |
DOIs | |
Publication status | Published - 2025 |
Bibliographical note
Funding Information:This work was supported by financial support from the Lundbeck Foundation (grant R277\u20102018\u2010260 to P.W.), the Novo Nordisk Foundation (grant NNF19SA0057841 to P.W., B.F. and B.R.K.), and the Drug Research Academy. We thank Alberte Cecilie Linnet Nielsen and Nane Griem\u2010Krey for their technical assistance. Finally, we would like to thank Casper T. Hansen for valuable input to the overall project.
Publisher Copyright:
© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.
Keywords
- (E)-2-(5-hydroxy-2-phenyl-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (Ph-HTBA)
- 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA)
- Angelman syndrome (AS)
- AS-related behaviour
- Ca/CaM-dependent kinase II alpha (CaMKIIα)
- hub domain