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bioRxiv · 10.1101/2025.02.06.636849

Identifying JNK-regulated phosphoproteome markers of anxiety-like behaviour in mouse hippocampus

Hong, Y.·Flinkman, D.·Deshpande, P.·Fagerholm, V.·Varidaki, A.·Heemeryck, P.·Sourander, C.·JAmes, P.·Coffey, E.
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Abstract

JNKs mediate neuronal damage in neurodegenerative disease and inhibitors of JNK1 have shown anxiolytic and anti-depressive effects in mice. Here, we analyze the phosphoproteomes of hippocampus and nucleus accumbens from DJNKI-1 (JNK inhibitor)-infused mice. We correlate phospho-site changes with anxiety-like behaviours in the elevated plus maze and light-dark test and identify unique changes in responder mice. Among the DJNKI-1 regulated phosphosites, several lie within GSK3 motifs and are exclusively down-regulated. Consistent with this, GSK3{beta} is inhibited and AKT activated. Importantly, we detect multilevel regulation of glucose metabolism enzymes including increased PDPK1-S241 phosphorylation, and a 5-fold increase in pyruvate dehydrogenase (PDHA1)-S-293 phosphorylation, signifying its inhibition. This suggests that JNK inhibitor drives a metabolic transformation to the neuronal Warburg response. This and a range of identified synaptic and cytoskeletal protein phosphosite changes are discussed in the context of JNK-regulated anxiety responses. The annotated hippocampal and nucleus accumbens phosphoproteomes described here will support a mechanistic understanding of the JNK pathway for future studies of brain disorders.

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Hong, Y., Flinkman, D., Deshpande, P., Fagerholm, V., Varidaki, A., Heemeryck, P., Sourander, C., JAmes, P., Coffey, E.. 2025-02-06. Identifying JNK-regulated phosphoproteome markers of anxiety-like behaviour in mouse hippocampus. https://doi.org/10.1101/2025.02.06.636849

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