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