Investigations into novel functions of JNK in neurons: Regulation of post-synaptic scaffold proteins by JNK3
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
In an essential set of experiments, we focussed on the functional links between JNK3 and the synaptic scaffold molecule SAP102. We demonstrated that the dynamics of SAP102 are negatively regulated by JNK inhibition, that SAP102 is a direct phosphorylation target of JNK3, and that SAP102 regulation by JNK is restricted to neurons that harbour mature synapses. We further demonstrate that SAP102 and JNK3 cooperate in the regulated trafficking of kainate receptors to the cell membrane. Specifically, we observe that SAP102, JNK3, and the kainate receptor subunit GluK2 exhibit overlapping expression at synaptic sites, and that modulating JNK activity influences the surface expression of the kainate receptor subunit GluK2 in a neuronal context. We also show that SAP102 participates in this process in a JNK-dependent fashion. In summary, our data support a model in which JNK-mediated regulation of SAP102 influences the dynamic trafficking of kainate receptors to postsynaptic sites, and thus shed light on common pathophysiological mechanisms underlying the cognitive developmental defects associated with diverse mutations. The results of this study contribute to our understanding of disease pathology in a specific subset of monogenic neurodevelopmental disorders. Importantly, our work highlights specific disease mechanisms that may be directly relevant for diverse genetic forms of cognitive delay, thus illuminating novel pathways that could serve as targets for the development of therapies for a broad spectrum of developmental disturbances. Moreover, our work contributes to the basic understanding of the physiological correlates of JNK inhibition; it is thus highly relevant for understanding the putative side effects of JNK inhibitors that are currently implemented in clinical trials for diverse diseases.
Publications
- Protein kinase C regulates AMPA receptor auxiliary protein Shisa9/CKAMP44 through interactions with neuronal scaffold PICK1. FEBS Open Bio, 2017. 7: p. 1234- 1245
Kunde, SA, Rademacher, N, Zieger, H, and Shoichet, SA
(See online at https://doi.org/10.1002/2211-5463.12261) - Intramolecular domain dynamics regulate synaptic MAGUK protein interactions. Elife, 2019. 8
Rademacher, N, Kuropka, B, Kunde, SA, Wahl, MC, Freund, C, and Shoichet, SA
(See online at https://doi.org/10.7554/eLife.41299) - Disease-associated synaptic scaffold protein CNK2 modulates PSD size and influences localisation of the regulatory kinase TNIK. Sci Rep, 2020. 10: p. 5709
Zieger, HL, Kunde, SA, Rademacher, N, Schmerl, B, and Shoichet, SA
(See online at https://doi.org/10.1038/s41598-020-62207-4) - The postsynaptic MAGUK scaffold protein MPP2 organises a distinct interactome that incorporates GABAA receptors at the periphery of excitatory synapses. bioRxiv, 2020
Schmerl, B, Gimber, N, Kuropka, B, Rentsch, J, Kunde, SA, Ewers, H, Freund, C, Schmoranzer, J, Rademacher, N, and Shoichet, SA
(See online at https://doi.org/10.1101/2020.05.29.123034) - JNK activity modulates postsynaptic scaffold protein SAP102 and kainate receptor dynamics in dendritic spines. bioRxiv, 2021
Kunde, SA, Schmerl, B, Ahmadyar E, Rademacher N, Zieger, HL, Shoichet, SA
(See online at https://doi.org/10.1101/2021.04.30.442109)
