Signaling peptides for brain diseases: Delivery and action

Title : Signaling peptides for brain diseases: Delivery and action

Abstract:

Arrestins were discovered as the key proteins responsible for the shutoff of the G protein-dependent signaling by G protein-coupled receptors (GPCRs). Later it was discovered that arrestins 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. We show that short peptides derived from the JNK3-binding region of arrestin-3 effectively mimic the full-length arrestin-3 protein in the ability to activate the JNK pathway. 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. Therefore, such peptides should act as selective inhibitors of arrestin-3-dependent activation of JNK3. We recently found that arrestin-3-dependent JNK activation is a contributing factor to L-DOPA-induced dyskinesia (LID), a severe side effect of the most commonly used L-DOPA therapy in Parkinson’s disease. We show that lentivirus-mediated delivery of peptides activating JNK3 promote LID, whereas inhibitory peptides alleviate it in animal models of LID without interfering with the beneficial effect of L-DOPA. 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. We will show the data on the effectiveness of inhibitory arrestin-3-derived peptides rendered cell penetrating as anti-LID therapeutics. The issue of the best way of delivering the peptide therapeutics into the brain will be addressed.

Biography:

Dr. Eugenia V Gurevich completed her doctorate in neuroscience in Moscow State University. She trained as a postdoctoral fellow with Dr. Jeffrey Joyce at the University of Pennsylvania, Pennsylvania, USA, and then accepted the position as the Brain Bank Director and Staff Scientist at Sun Health Research Institute in Sun City, Arizona, where she conducted research on dopamine receptor functions in Parkinson’s disease and schizophrenia with the focus on postmortem studies of the human brain. Since 2003, Dr. Gurevich is a faculty member of the Department of Pharmacology at Vanderbilt University, Tennessee, (Assistant Professor 2003-2009, Associate Professor from 2009), where she conducts research on the regulation of dopaminergic signaling in the normal and diseased brain. She is particularly interested in the functional role of proteins, G protein-coupled receptor kinases (GRKs) and arrestins, controlling desensitization of G protein-coupled receptors n neural pathologies such as Parkinson’s disease, L-DOPA-induced dyskinesia, and drug addiction. She is an expert on the use of viral gene transfer technology to induce protein expression or knockdown in the brain of living animals. Dr. Gurevich has pioneered the study of the role of GRKs and arrestins in L-DOPA-induced dyskinesia with the goal of targeting these proteins to control dyskinesia and other L-DOPA-induced motor complications. This work may eventually lead to the development of novel therapies for Parkinson’s disease and drug discoveries targeting GRK proteins.