CaMKIIα hub ligands are unable to reverse known phenotypes in Angelman syndrome mice

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00603644" target="_blank" >RIV/61388963:_____/25:00603644 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1111/bcpt.14112" target="_blank" >https://doi.org/10.1111/bcpt.14112</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/bcpt.14112" target="_blank" >10.1111/bcpt.14112</a>

Jazyk výsledku

angličtina

Název v původním jazyce

CaMKIIα hub ligands are unable to reverse known phenotypes in Angelman syndrome mice

Popis výsledku v původním jazyce

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 (CaMKII alpha) 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 CaMKII alpha 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 CaMKII alpha is known to be dysregulated. Here, we sought to investigate whether pharmacological modulation with these prototypical CaMKII alpha 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 CaMKII alpha autophosphorylation in AS mouse brain tissue. Taken together our results indicate that pharmacological modulation of CaMKII alpha via the selective hub ligands used here is not a viable treatment strategy in AS.

Název v anglickém jazyce

CaMKIIα hub ligands are unable to reverse known phenotypes in Angelman syndrome mice

Popis výsledku anglicky

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 (CaMKII alpha) 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 CaMKII alpha 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 CaMKII alpha is known to be dysregulated. Here, we sought to investigate whether pharmacological modulation with these prototypical CaMKII alpha 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 CaMKII alpha autophosphorylation in AS mouse brain tissue. Taken together our results indicate that pharmacological modulation of CaMKII alpha via the selective hub ligands used here is not a viable treatment strategy in AS.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10406 - Analytical chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Basic & Clinical Pharmacology & Toxicology

ISSN

1742-7835

e-ISSN

1742-7843

Svazek periodika

136

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

e14112

Kód UT WoS článku

001388144900022

EID výsledku v databázi Scopus

2-s2.0-85211614839