Delivery of the aggregate inhibitor peptide QBP1 into the mouse brain using PTDs and its therapeutic effect on polyglutamine disease mice.
The polyglutamine (polyQ) diseases are neurodegenerative diseases caused by proteins with an abnormally expanded polyQ stretch, which triggers abnormal aggregation of these proteins in the brain. We previously showed that the polyQ-binding peptide QBP1 inhibits polyQ aggregation, and further that administration of QBP1 fused with a protein transduction domain (PTD) suppresses polyQ-induced neurodegeneration in Drosophila. As the next step towards developing a therapy using QBP1, we investigated the delivery of PTD-QBP1 to the mouse brain upon its administration. Here we successfully detected delivery of PTD-QBP1 into mouse brain cells upon its single intracerebroventricular injection. In addition, long-term administration of PTD-QBP1 to polyQ disease mice improved their weight loss phenotype, suggesting a possible therapeutic effect. Our study indicates the potential of PTD-mediated delivery of QBP1 as a therapeutic strategy for the currently untreatable polyQ diseases.
Popiel
H Akiko
HA
Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Nagai
Yoshitaka
Y
Fujikake
Nobuhiro
N
Toda
Tatsushi
T
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010641:Phenotype; D017434:Protein Structure, Tertiary / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D009842:Oligopeptides; D010455:Peptides; D011993:Recombinant Fusion Proteins; C407346:polyglutamine-binding protein 1; C097188:polyglutamine