Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice.

Abstract

Gene transfer has proven to be an effective neurobiological tool in a number of neurodegenerative diseases, but it is not known if it can correct a sleep disorder. Narcolepsy is a neurodegenerative sleep disorder linked to the loss of neurons containing the neuropeptide orexin, also known as hypocretin. Here, a replication-defective herpes simplex virus-1 amplicon-based vector was constructed to transfer the gene for mouse prepro-orexin into mice with a genetic deletion of the orexin gene. After in vitro tests confirmed successful gene transfer into cells, the gene vector was delivered to the lateral hypothalamus of orexin knockout (KO) mice where the orexin peptide was robustly expressed in the somata and processes of numerous neurons, and the peptide product was detected in the cerebrospinal fluid. During the 4-day life-span of the vector the incidence of cataplexy declined by 60%, and the levels of rapid eye movement sleep during the second half of the night were similar to levels in wild-type mice, indicating that narcoleptic sleep-wake behavior in orexin KO mice can be improved by targeted gene transfer.

• Authors: Meng Liu, Stephen Thankachan, Satvinder Kaur, Suraiya Begum, Carlos Blanco-Centurion, Takeshi Sakurai, Masashi Yanagisawa, Rachael Neve, Priyattam J Shiromani
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 28 Issue 7 Pg. 1382-93 (Oct 2008) ISSN: 1460-9568 [Electronic] France
• PMID: 18973565 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Neuropeptides
• Orexins
• Recombinant Fusion Proteins
• enhanced green fluorescent protein
• Green Fluorescent Proteins

Topics

• Animals
• Cells, Cultured
• Disease Models, Animal
• Gene Transfer Techniques
• Genes, Reporter (genetics)
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Green Fluorescent Proteins (genetics)
• Hypothalamic Area, Lateral (cytology, metabolism, surgery)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Narcolepsy (genetics, metabolism, therapy)
• Neurons (metabolism)
• Neuropeptides (genetics, metabolism)
• Orexins
• Rats
• Rats, Sprague-Dawley
• Recombinant Fusion Proteins (genetics)
• Sleep (genetics)
• Treatment Outcome