title: SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system.
abstract: BACKGROUND
  Dominant mutations in superoxide dismutase 1 (SOD1) cause degeneration of motor neurons in a subset of inherited amyotrophic lateral sclerosis (ALS). The pathogenetic process mediated by misfolded and/or aggregated mutant SOD1 polypeptides is hypothesized to be suppressed by protein refolding. This genetic study is aimed to test whether mutant SOD1-mediated ALS pathology recapitulated in mice could be alleviated by overexpressing a longevity-related deacetylase SIRT1 whose substrates include a transcription factor heat shock factor 1 (HSF1), the master regulator of the chaperone system.
  
  
  RESULTS
  We established a line of transgenic mice that chronically overexpress SIRT1 in the brain and spinal cord. While inducible HSP70 (HSP70i) was upregulated in the spinal cord of SIRT1 transgenic mice (PrP-Sirt1), no neurological and behavioral alterations were detected. To test hypothetical benefits of SIRT1 overexpression, we crossbred PrP-Sirt1 mice with two lines of ALS model mice: A high expression line that exhibits a severe phenotype (SOD1G93A-H) or a low expression line with a milder phenotype (SOD1G93A-L). The Sirt1 transgene conferred longer lifespan without altering the time of symptomatic onset in SOD1G93A-L. Biochemical analysis of the spinal cord revealed that SIRT1 induced HSP70i expression through deacetylation of HSF1 and that SOD1G93A-L/PrP-Sirt1 double transgenic mice contained less insoluble SOD1 than SOD1G93A-L mice. Parallel experiments showed that Sirt1 transgene could not rescue a more severe phenotype of SOD1G93A-H transgenic mice partly because their HSP70i level had peaked out.
  
  
  CONCLUSIONS
  The genetic supplementation of SIRT1 can ameliorate a mutant SOD1-linked ALS mouse model partly through the activation of the HSF1/HSP70i chaperone system. Future studies shall include testing potential benefits of pharmacological enhancement of the deacetylation activity of SIRT1 after the onset of the symptom.
authors.forename: Seiji
authors.initials: S
authors.lastname: Watanabe
authors.forename: Natsumi
authors.initials: N
authors.lastname: Ageta-Ishihara
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagatsu
authors.forename: Keizo
authors.initials: K
authors.lastname: Takao
authors.forename: Okiru
authors.initials: O
authors.lastname: Komine
authors.forename: Fumito
authors.initials: F
authors.lastname: Endo
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Hidemi
authors.initials: H
authors.lastname: Misawa
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikus, Nagoya 464-8601, Japan. kinoshita.makoto@c.mbox.nagoya-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
mesh_terms: D000107:Acetylation; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001522:Behavior, Animal; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D018628:Gene Dosage; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008136:Longevity; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D017510:Protein Folding; D056564:Sirtuin 1 / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C000606290:SOD1 protein, human; D014157:Transcription Factors; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1