Arrestin-3-assisted activation of JNK3 mediates dopaminergic behavioral sensitization.

In rodents with unilateral ablation of neurons supplying dopamine to the striatum, chronic treatment with the dopamine precursor L-DOPA induces a progressive increase of behavioral responses, a process known as behavioral sensitization. This sensitization is blunted in arrestin-3 knockout mice. Using virus-mediated gene delivery to the dopamine-depleted striatum of these mice, we find that the restoration of arrestin-3 fully rescues behavioral sensitization, whereas its mutant defective in c-Jun N-terminal kinase (JNK) activation does not. A 25-residue arrestin-3-derived peptide that facilitates JNK3 activation in cells, expressed ubiquitously or selectively in direct pathway striatal neurons, also fully rescues sensitization, whereas an inactive homologous arrestin-2-derived peptide does not. Behavioral rescue is accompanied by the restoration of JNK3 activity, as reflected by JNK-dependent phosphorylation of the transcription factor c-Jun in the dopamine-depleted striatum. Thus, arrestin-3-assisted JNK3 activation in direct pathway neurons is a critical element of the molecular mechanism underlying sensitization upon dopamine depletion and chronic L-DOPA treatment.

14-3-3 Proteins: Novel Pharmacological Targets in Neurodegenerative Diseases.

14-3-3 proteins are a family of proteins expressed throughout the body and implicated in many diseases, from cancer to neurodegenerative disorders. While these proteins do not have direct enzymatic activity, they form a hub for many signaling pathways via protein-protein interactions (PPIs). 14-3-3 interactions have proven difficult to target with traditional pharmacological methods due to the unique nature of their binding. However, recent advances in compound development utilizing a range of tools, from thermodynamic binding site analysis to computational molecular modeling techniques, have opened the door to targeting these interactions. Compounds are already being developed targeting 14-3-3 interactions with potential therapeutic implication for neurodegenerative disorders, but challenges still remain in optimizing specificity and target engagement to avoid unintended negative consequences arising from targeting 14-3-3 signaling networks.