Peptide-based therapeutics for the treatment of neurodegenerative diseases; challenges and opportunities

Title : Peptide-based therapeutics for the treatment of neurodegenerative diseases; challenges and opportunities

Abstract:

Arrestins were discovered as the key players in the desensitization of G protein-coupled receptors (GPCRs) by virtue of specific binding to active phosphorylated GPCRs and blocking further G protein activation. Both receptor-bound and free arrestins also initiate multiple signaling pathways, including mitogen activated protein (MAP) kinase pathways, by virtue of scaffolding the pathways’ components. One of the two ubiquitously expressed arrestin subtypes, arrestin-3, is the only isoform capable of activating the JNK pathway. Arrestin-3 can facilitate the activation of JNK family kinases independently of receptor binding. 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 scaffolds and inhibiting JNK3 activation via the dominant-negative mechanism. We recently found that arrestin-3-dependent JNK activation is a contributing factor to L-DOPA-induced dyskinesia, a severe side effect of the most commonly used L-DOPA therapy in Parkinson’s disease. Potential use of arrestin-3-derived peptides inhibiting the JNK activation as anti-dyskinetic therapy will be discussed. We will also discuss the potential of protein-derived peptides capable of fulfilling select functions of the parent multi-functional protein as therapeutic tools, specifically to target protein-protein interactions, which are notoriously hard to modulate with small molecule therapeutics. Finally, the issue of the best way of delivering the peptide therapeutics into the brain will be addressed.

Takeaway Notes:
• Other faculty could find this research helpful in their own studies of the signaling pathways involved in diseases, since this is a relative novel way to modulate the signaling;
• 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”.

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.