title: Hsp40 gene therapy exerts therapeutic effects on polyglutamine disease mice via a non-cell autonomous mechanism.
abstract: The polyglutamine (polyQ) diseases such as Huntington's disease (HD), are neurodegenerative diseases caused by proteins with an expanded polyQ stretch, which misfold and aggregate, and eventually accumulate as inclusion bodies within neurons. Molecules that inhibit polyQ protein misfolding/aggregation, such as Polyglutamine Binding Peptide 1 (QBP1) and molecular chaperones, have been shown to exert therapeutic effects in vivo by crossing of transgenic animals. Towards developing a therapy using these aggregation inhibitors, we here investigated the effect of viral vector-mediated gene therapy using QBP1 and molecular chaperones on polyQ disease model mice. We found that injection of adeno-associated virus type 5 (AAV5) expressing QBP1 or Hsp40 into the striatum both dramatically suppresses inclusion body formation in the HD mouse R6/2. AAV5-Hsp40 injection also ameliorated the motor impairment and extended the lifespan of R6/2 mice. Unexpectedly, we found even in virus non-infected cells that AAV5-Hsp40 appreciably suppresses inclusion body formation, suggesting a non-cell autonomous therapeutic effect. We further show that Hsp40 inhibits secretion of the polyQ protein from cultured cells, implying that it inhibits the recently suggested cell-cell transmission of the polyQ protein. Our results demonstrate for the first time the therapeutic effect of Hsp40 gene therapy on the neurological phenotypes of polyQ disease mice.
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: H Akiko
authors.initials: HA
authors.lastname: Popiel
authors.forename: Toshihide
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Chiyomi
authors.initials: C
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamane
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D000229:Dependovirus / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000627:therapeutic use*; D018737:Hand Strength / Q000502:physiology; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002479:Inclusion Bodies / Q000378:metabolism; D008136:Longevity; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009842:Oligopeptides / Q000235:genetics / Q000627:therapeutic use; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D015431:Weight Loss
chemical_list: D050956:HSP40 Heat-Shock Proteins; D009842:Oligopeptides; D010455:Peptides; C407346:polyglutamine-binding protein 1; C097188:polyglutamine