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: Seiji Watanabe, Natsumi Ageta-Ishihara, Shinji Nagatsu, Keizo Takao, Okiru Komine, Fumito Endo, Tsuyoshi Miyakawa, Hidemi Misawa, Ryosuke Takahashi, Makoto Kinoshita, Koji Yamanaka
• Journal: Molecular brain (Mol Brain) Vol. 7 Pg. 62 (Aug 29 2014) ISSN: 1756-6606 [Electronic] England
• PMID: 25167838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• HSF1 protein, human
• HSP70 Heat-Shock Proteins
• Heat Shock Transcription Factors
• SOD1 protein, human
• Transcription Factors
• Sod1 protein, mouse
• Superoxide Dismutase
• Superoxide Dismutase-1
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Acetylation
• Amyotrophic Lateral Sclerosis (metabolism, pathology)
• Animals
• Behavior, Animal
• DNA-Binding Proteins (metabolism)
• Disease Models, Animal
• Gene Dosage
• HSP70 Heat-Shock Proteins (metabolism)
• Heat Shock Transcription Factors
• Humans
• Longevity
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation (genetics)
• Promoter Regions, Genetic (genetics)
• Protein Folding
• Sirtuin 1 (metabolism)
• Spinal Cord (pathology)
• Superoxide Dismutase (genetics)
• Superoxide Dismutase-1
• Transcription Factors (metabolism)
• Up-Regulation