Phosphoproteomics implicates glutamatergic and dopaminergic signalling in the antidepressant-like properties of the iron chelator deferiprone

• Published in: Neuropharmacology Vol. 246; p. 109837
• Main Authors: Uzungil, Volkan, Luza, Sandra, Opazo, Carlos M., Mees, Isaline, Li, Shanshan, Ang, Ching-Seng, Williamson, Nicholas A., Bush, Ashley I., Hannan, Anthony J., Renoir, Thibault
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.03.2024
• Subjects: 5-HTT KO; Antidepressant; Dopamine; Glutamate; Phosphoproteomics; Antidepressant; Dopamine; Phosphoproteomics; Glutamate; 5-HTT KO
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2024.109837

Current antidepressants have limitations due to insufficient efficacy and delay before improvement in symptoms. Polymorphisms of the serotonin transporter (5-HTT) gene have been linked to depression (when combined with stressful life events) and altered response to selective serotonergic reuptake inhibitors. We have previously revealed the antidepressant-like properties of the iron chelator deferiprone in the 5-HTT knock-out (KO) mouse model of depression. Furthermore, deferiprone was found to alter neural activity in the prefrontal cortex of both wild-type (WT) and 5-HTT KO mice. In the current study, we examined the molecular effects of acute deferiprone treatment in the prefrontal cortex of both genotypes via phosphoproteomics analysis. In WT mice treated with deferiprone, there were 22 differentially expressed phosphosites, with gene ontology analysis implicating cytoskeletal proteins. In 5-HTT KO mice treated with deferiprone, we found 33 differentially expressed phosphosites. Gene ontology analyses revealed phosphoproteins that were predominantly involved in synaptic and glutamatergic signalling. In a drug-naïve cohort (without deferiprone administration), the analysis revealed 21 differentially expressed phosphosites in 5-HTT KO compared to WT mice. We confirmed the deferiprone-induced increase in tyrosine hydroxylase serine 40 residue phosphorylation (pTH-Ser40) (initially revealed in our phosphoproteomics study) by Western blot analysis, with deferiprone increasing pTH-Ser40 expression in WT and 5-HTT KO mice. As glutamatergic and synaptic signalling are dysfunctional in 5-HTT KO mice (and are the target of fast-acting antidepressant drugs such as ketamine), these molecular effects may underpin deferiprone's antidepressant-like properties. Furthermore, dopaminergic signalling may also be involved in deferiprone's antidepressant-like properties. •Phosphoproteomics reveals molecular markers involved in acute deferiprone treatment in prefrontal cortex.•Deferiprone phosphorylates proteins involved in dopamine and glutamate signalling in 5-HTT KO mice.•Deferiprone phosphorylates proteins involved in cytoskeletal organisation in WT mice.•Western blot confirms increased phosphorylation of tyrosine hydroxylase serine 40 phosphosite by deferiprone.