SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system

Seiji Watanabe, Natsumi Ageta-Ishihara, Shinji Nagatsu, Keizo Takao, Okiru Komine, Fumito Endo, Tsuyoshi Miyakawa, Hidemi Misawa, Ryosuke Takahashi, Makoto Kinoshita, Koji Yamanaka

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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 (SOD1 G93A -H) or a low expression line with a milder phenotype (SOD1 G93A -L). The Sirt1 transgene conferred longer lifespan without altering the time of symptomatic onset in SOD1 G93A -L. Biochemical analysis of the spinal cord revealed that SIRT1 induced HSP70i expression through deacetylation of HSF1 and that SOD1 G93A -L/PrP-Sirt1 double transgenic mice contained less insoluble SOD1 than SOD1 G93A -L mice. Parallel experiments showed that Sirt1 transgene could not rescue a more severe phenotype of SOD1 G93A -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.

Original languageEnglish
Article number62
JournalMolecular Brain
Volume7
Issue number1
DOIs
Publication statusPublished - 29-08-2014

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Amyotrophic Lateral Sclerosis
Shock
Hot Temperature
Transgenic Mice
Spinal Cord
Transgenes
Phenotype
Superoxide Dismutase-1
Protein Refolding
Motor Neurons
Pharmacology
Pathology
Peptides
Mutation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Watanabe, S., Ageta-Ishihara, N., Nagatsu, S., Takao, K., Komine, O., Endo, F., ... Yamanaka, K. (2014). SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system. Molecular Brain, 7(1), [62]. https://doi.org/10.1186/s13041-014-0062-1
Watanabe, Seiji ; Ageta-Ishihara, Natsumi ; Nagatsu, Shinji ; Takao, Keizo ; Komine, Okiru ; Endo, Fumito ; Miyakawa, Tsuyoshi ; Misawa, Hidemi ; Takahashi, Ryosuke ; Kinoshita, Makoto ; Yamanaka, Koji. / SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system. In: Molecular Brain. 2014 ; Vol. 7, No. 1.
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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 (SOD1 G93A -H) or a low expression line with a milder phenotype (SOD1 G93A -L). The Sirt1 transgene conferred longer lifespan without altering the time of symptomatic onset in SOD1 G93A -L. Biochemical analysis of the spinal cord revealed that SIRT1 induced HSP70i expression through deacetylation of HSF1 and that SOD1 G93A -L/PrP-Sirt1 double transgenic mice contained less insoluble SOD1 than SOD1 G93A -L mice. Parallel experiments showed that Sirt1 transgene could not rescue a more severe phenotype of SOD1 G93A -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.",
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Watanabe, S, Ageta-Ishihara, N, Nagatsu, S, Takao, K, Komine, O, Endo, F, Miyakawa, T, Misawa, H, Takahashi, R, Kinoshita, M & Yamanaka, K 2014, 'SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system', Molecular Brain, vol. 7, no. 1, 62. https://doi.org/10.1186/s13041-014-0062-1

SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system. / Watanabe, Seiji; Ageta-Ishihara, Natsumi; Nagatsu, Shinji; Takao, Keizo; Komine, Okiru; Endo, Fumito; Miyakawa, Tsuyoshi; Misawa, Hidemi; Takahashi, Ryosuke; Kinoshita, Makoto; Yamanaka, Koji.

In: Molecular Brain, Vol. 7, No. 1, 62, 29.08.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system

AU - Watanabe, Seiji

AU - Ageta-Ishihara, Natsumi

AU - Nagatsu, Shinji

AU - Takao, Keizo

AU - Komine, Okiru

AU - Endo, Fumito

AU - Miyakawa, Tsuyoshi

AU - Misawa, Hidemi

AU - Takahashi, Ryosuke

AU - Kinoshita, Makoto

AU - Yamanaka, Koji

PY - 2014/8/29

Y1 - 2014/8/29

N2 - 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 (SOD1 G93A -H) or a low expression line with a milder phenotype (SOD1 G93A -L). The Sirt1 transgene conferred longer lifespan without altering the time of symptomatic onset in SOD1 G93A -L. Biochemical analysis of the spinal cord revealed that SIRT1 induced HSP70i expression through deacetylation of HSF1 and that SOD1 G93A -L/PrP-Sirt1 double transgenic mice contained less insoluble SOD1 than SOD1 G93A -L mice. Parallel experiments showed that Sirt1 transgene could not rescue a more severe phenotype of SOD1 G93A -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.

AB - 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 (SOD1 G93A -H) or a low expression line with a milder phenotype (SOD1 G93A -L). The Sirt1 transgene conferred longer lifespan without altering the time of symptomatic onset in SOD1 G93A -L. Biochemical analysis of the spinal cord revealed that SIRT1 induced HSP70i expression through deacetylation of HSF1 and that SOD1 G93A -L/PrP-Sirt1 double transgenic mice contained less insoluble SOD1 than SOD1 G93A -L mice. Parallel experiments showed that Sirt1 transgene could not rescue a more severe phenotype of SOD1 G93A -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.

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