Title : Arrestin-3-dependent activation of the JNK pathway as a therapeutic target for L-DOPA-induced dyskinesia
Arrestins were first discovered as the key proteins responsible for the shutoff of the G protein-dependent signaling by G protein-coupled receptors. Later arrestins were found to regulate multiple signaling pathways, including mitogen activated protein (MAP) kinase pathways, by scaffolding the pathways’ components. One of the two ubiquitously expressed arrestin subtypes, arrestin-3, is the only isoform capable of activating the JNK pathway, with the preference for the JNK3 neuro specific isoform. L-DOPA-induced dyskinesia (LID) is a severe side effect of the most commonly used L-DOPA therapy in Parkinson’s disease that severely compromised the quality of life of PD patients. We recently found that mice lacking arrestin-3 (KO) display lower level of LID in rodent models of LID but preserved antiparkinsonian effect of L-DOPA. These data suggested that arrestin-3 contributes uniquely to LID and could be a selective target for anti-LID therapy. The lentivirus-mediated delivery of wild type (WT) arrestin-3 fully restored LID, whereas the expression of mutant arrestin-3 defective in the JNK activation was ineffective pointing to the role of arrestin-3-dependent JNK activation in LID. We further probed the contribution of arrestin-3-dependent JNK activation by using specific short peptides derived from the JNK3-binding region of arrestin-3 that effectively mimic the full-length arrestin-3 protein in the ability to activate the JNK pathway. These peptides also fully restored LID when expressed in the motor striatum of arrestin-3 KO mice. Further deletion of a few amino acids yields peptides that bind some, but not all, kinases in the JNK pathway, thereby recruiting them away from productive arrestin-3-dependent scaffolds and inhibiting JNK3 activation via the dominant-negative mechanism. Such peptides ameliorated LID in animal models of LID acting as selective inhibitors of arrestin-3-dependent activation of JNK3. Our data suggest that arrestin-3-depepndent activation of JNK3 is an important mechanisms mediating LID and could be a promising target for anti-LID therapy. The importance of this mechanism is further underscored by the finding that arrestin-3 is not required for the anti-parkinsonian, beneficial effect of L-DOPA, which is fully preserved in arrestin-3 KO mice. Furthermore, these data suggest that signaling peptides could be used as highly selective therapeutics for brain diseases. Such protein-derived peptides capable of fulfilling select functions of the parent multi-functional protein have a great potential as therapeutic tools, specifically to target protein-protein interactions, which are notoriously hard to modulate with small molecule therapeutics.
Audience take away:
- Our data present a novel pathway implicated in LID that could also be a promising target for anti-LID therapy.
- Our studies demonstrate a constructive way or using mutant proteins combined with gene delivery and genetically engineered mouse strains to elucidate the contribution of specific signaling pathways to the brain diseases.
- Our experience in using peptides to treat a brain disease would be helpful to other scientists interested in neurodegenerative and other brain disorders;
- The design of the therapeutics targeting protein-protein interactions could also be advanced by our studies. Since most regulatory functions in the cells are performed via protein-protein interactions, this would help to open up a large pool of novel therapeutic targets that would become “druggable”.