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1 Acta Neurobiologiae Experimentalis

1 2019

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Role of Arc phosphorylation in structural plasticity

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Gozdz A. , Nikolaienko O. , Urbanska M. , Cymerman I. , Sitkiewicz E. , Blazejczyk M. , Dadlez M. , Bramham C. , Jaworski J.

nr Suppl.1

Arc protein was shown to control synaptic AMPA receptor content, dendritic spine maintenance, and structure. Given its importance for neuronal function, Arc protein expression has to be tightly regulated and it occurs via ubiquitination and proteasomal degradation. Glycogen synthase kinases α and β (GSK3α/β) are serine‑threonine kinases abundantly expressed in neuronal cells, crucial for neuronal plasticity. GSK3α/β phosphorylate and prime numerous proteins for ubiquitination and degradation, however until now no interaction between Arc and GSK3α/β has been reported. The present study aims to address if and how GSK3α/β affects Arc protein expression, and whether their interaction plays a role in the regulation of dendritic spine morphology. GSK3-dependent Arc protein degradation and the effects of this process on dendritic spine morphology were studied in cultured embryonic cortical and hippocampal murine neurons upon NMDA receptors stimulation. Arc protein residues modified in GSK3‑dependent manner were identified by mass spectrometry. Obtained results were confirmed by in vitro kinase assays and the use of anti‑phospho‑Arc antibodies. We observed higher Arc levels in neurons exposed to NMDA upon GSK3α/β inhibition. In vitro kinase assays revealed that Arc is a substrate for GSK3α and β. Further analysis identified four residues phosphorylated by GSK3α/β (S170, T175, T368, T380) and one ubiquitinated in GSK3‑dependent manner (K136). Finally, we demonstrated that quadruple phosphodeficient mutant of Arc, as well as ubiquitination‑resistant Arc, were more stable in neurons upon NMDAR stimulation, and produced significant thinning of dendritic spine head. Our results identify GSK3α/β‑catalyzed Arc phosphorylation and degradation as a novel mechanism for controlling the duration of Arc expression and its effect on dendritic spine structure.