Use of cell-permeable peptides to prevent neuronal degeneration.
The loss of neurons is a hallmark of neurodegenerative disorders and evidence suggests that this occurs through an apoptotic mechanism. Following an insult, neuronal cells activate signal transduction pathways that lead to cell death and the establishment of the pathological state. The mechanisms underlying the cell-death response involve protein kinases, which phosphorylate many substrates and culminate in changes in gene expression. Traditionally, attempts at blocking such signaling targeted the phosphorylation of the substrates. However, preventing the interaction between two proteins using specific peptides might block the function of key mediators in signaling cascades. A cell-permeable peptide designed specifically to inhibit c-Jun N-terminal kinase action proved successful in in vivo models of neuronal degeneration following ischemia. Here, the recent findings that highlight the potential of this approach for therapeutic application are reviewed.
Borsello
Tiziana
T
IBCM, University of Lausanne, Lausanne, Switzerland. Tiziana.Borsello@ibcm.unil.ch
Bonny
Christophe
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002463:Cell Membrane Permeability; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D018696:Neuroprotective Agents; D010455:Peptides; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases